Drug-induced

Movement Disorders
Mishal Abu Al-Melh, MD, FRCPC
19 May 16
 Introduction

• Drug-induced movement disorders are varied

and can be caused by a number of
medications that alter central nervous system
neurochemistry (D2 receptor blockade)
• Include:
• Parkinsonism
• Tardive phenomena
• Chorea
• Dystonia
• Tremor
• Akathisia
• Myoclonus
• Tics, and
• Neuroleptic malignant syndrome
• The movements can be acute or chronic
phenomena.

• Can be focal, hemi-, or generalized in nature.

• With the exception of the tardive phenomenon,

can usually be treated by elimination of the
offending medication.
• 1. Acute:
• Akathisia
• Dystonia
• 2. Overdosage:
• Drug-induced Parkinsonism
• 3. Neuroleptic malignant syndrome
• Chronic: Tardive Syndromes
• Dyskinesia

• Akathisia

• Dystonia
• Tremors

• Tics

• Myoclonus
 Acute Dystonia

• Are sustained muscle contractions,

frequently causing twisting and repetitive
movements, or abnormal postures.
• Earliest abnormal involuntary movement to
appear after initiation of dopamine receptor
antagonist therapy.
• Can be associated with oculogyric crisis.
• The reaction may occur after the first dose.
• In 50%, occurs within 48 hours.
• In 90%, it occurs by 5 days after starting
the therapy.
• High incidence rate ( >50%) with highly
potent dopamine receptor blockers such as
haloperidol.
• Acute dystonia was significantly higher in
males than in females (77.8% vs. 28.6%, P
< 0.05).
• Younger males (≤30 years) had an
extremely high incidence (91.7%).
• The incidence is much lower with the
atypical antipsychotics.
• Second generation antipsychotics were
associated with a significantly lower risk of
acute dystonia (relative risk = 0.19) and
acute akathisia (relative risk = 0.25),
compared with haloperidol alone.

• Serotonergic agents have also been

reported to induce acute dystonic
reactions.
• Tetrabenazine (TBZ), has been reported to
induce acute dystonic reactions.

• In addition to depleting dopamine, TBZ

blocks dopamine receptors.
• Acute dystonia mostly affect the:

• Ocular muscles (oculogyric crisis),

• Face, jaw, tongue, neck, and trunk, and
• Less often the limbs.
• A typical acute dystonic reaction may
consist of :
• head tilt backward or sideways with tongue
protrusion and
• forced opening of the mouth,
• often with arching of trunk and
• ocular deviation upward or laterally
• Hypothesis:
• After neuroleptic dose:
• 1- Surge of dopamine release
• 2- Denervation supersensitivity of
postsynaptic dopamine receptors
• 3- Result in markedly increased striatal
dopaminergic activity at about 20–40 hours
• Symptoms can be relieved within minutes
after parenteral anticholinergics or
antihistaminics. D/c offending drug.
• Diphenhydramine 50 mg, benztropine
mesylate or biperiden 1–2 mg is given
intravenously.
• Intravenous diazepam
• If untreated, the majority of cases still resolve
spontaneously in 12–48 hours.

• Dopamine receptor antagonists with high

anticholinergic activities have low incidence rates
of acute dystonic reactions.

• Prophylactic use of anticholinergics especially in

the young and on high potency drugs.
 Acute Akathisia

• A hyperkinetic (sensorimotor) movement disorder

characterized by restlessness and the irresistible urge
to move.
• May be an acute, subacute, or tardive phenomenon.
• Might reflect an alteration of the dopaminergic
mesolimbic system.
• Occurs with medications that alter central nervous
system dopamine levels ( 20%-30%)
• Including: typical > atypical neuroleptics, antiemetic
agents, reserpine, and tetrabenazine.
• The motor aspect of akathisia (akathitic
movements):

• Excessive movements that are complex,

semipurposeful, stereotypic, and repetitive,
suppressible and decrease with distraction.

• Akathisia is also seen in patients with Parkinson

disease, cocaine abuse, and SSRI use. (Daras et
al., 1994), ands (Poyurovsky et al., 1995)
• Acute akathisia is self-limited, disappearing on
discontinuation of neuroleptics.
• First line therapies include:
• Propranolol : Below 80 mg/day
• Mirtazipine : A literature search revealed
mirtazapine to be effective and superior to
propranolol (43.3% vs. 30.0%) (Hieber et al.,
2008)
• Trazadone
• Clonidine

• Mianserin : 5 HT2 antagonist

• Nicotine patch

• Amantadine

• Tetrabenazine/reserpine

• Gabapentin
• Zolpidem : GABA-mimetic drug & selective
agonist of the BZD receptor.

• Fluvoxamine, a sigma-1 agonist

• Potential future class of medications that may be

effective in treating akathisia is the adenosine A2a
antagonist group.

• DBS +/-
• One study compared the efficacy of B6, mianserin
and placebo in the treatment of acute akathisia
• Sixty schizophrenia and schizoaffective in-patients
with akathisia were randomized to receive vitamin
B6 1200 mg/d, mianserin 15 mg/d, or placebo for
5 days, in a double-blind design
• Compared with the placebo group, the vitamin B6-
treated and mianserin-treated patients showed a
significant improvement in the subjective
symptoms (P < 0.0001)
 Drug-induced
Parkinsonism
• Clinically indistinguishable from idiopathic
Parkinson’s disease.

• May occur as a symmetric or asymmetric

phenomenon.

• Tremor, rigidity, bradykinesia, and less commonly

postural instability are common features.

• Due to medications that affect presynaptic,

synaptic, or postsynaptic dopamine levels.
• Women are affected almost twice as frequently as
men.

• Occurs increasingly with advanced age in parallel with

the incidence of idiopathic PD.

• All DRBAs can induce parkinsonism, except clozapine

(there are only rare reports with clozapine) Factor and
Friedman, 1997)
• It can be either a subacute or chronic condition.
• In patients at risk, 50% to 70% will develop
symptoms within 1 month of starting therapy and
90% within 3 months (Ayd, 1961).
• The most effective treatment for drug-induced
parkinsonism is elimination of the offending
medication.
• If symptoms persist, the patient most likely has
subclinical parkinsonism that was unmasked.
• Neuroimaging with [18F]fluoro- dopa positron
emission tomography :
• Patients with pure drug- induced parkinsonism will
have normalization of their radioactive dopa
uptake in the basal ganglia after elimination of
precipitating drugs.
• While patients with unmasking of an underlying
parkinsonism will have persistent diminished
uptake after elimination of the precipitating
medication (Burn and Brook, 1993)
• Parkinsonism from neuroleptics is typically
reversible when the medication is reduced or
discontinued.

• Sometimes, the reversal can take many months;

an interval of up to 18 months has been noted in
the literature (Fleming et al., 1970).
• SSRIs can sometimes worsen parkinsonism in patients
with PD (Meco et al., 1994).
• Occasionally can induce parkinsonism in patients who
never had symptoms of PD (Coulter and Pillans, 1995;
DiRocco et al., 1998)

• In an intensive monitoring program in New Zealand of

the SSRI drug fluoxetine over a 4-year period, there
were 15 reports of parkinsonism in 5555 patients who
were exposed to the drug (Coulter and Pillans, 1995)
• The explanation for inducing or enhancing
parkinsonism is that:

• Increased serotonergic activity in the substantia

nigra will inhibit dopamine-containing neurons,

• Thus causing functional dopamine deficiency in

the nigrostriatal pathway (Baldessarini and Marsh,
1992
• Treatment:

• Stop the offending drug

• Usually initiated with anticholinergics or

amantadine.

• Levodopa & dopamine agonist not effective

except in cases who were on dopamine depletors
( reserpine).
 Neuroleptic Malignant
Syndrome
• NMS is an idiosyncratic reaction that can sometimes be life-
threatening.

• Clinical triad consists of:

• (1) Hyperthermia, usually with other autonomic dysfunctions

such as tachycardia, diaphoresis, and labile blood pressure

• (2) Extrapyramidal signs, usually increased muscle tone of

rigidity or dystonia, often with accompanying elevation of
muscle enzymes; and

• (3) Alteration of mental status, such as agitation, inattention,

and confusion.
• DSM-IV:
• Increased temperature and muscle rigidity
accompanied by two or more of the following:
• 1- Diaphoresis
• 2- Tremor
• 3- Dysphagia
• 4- Altered mental status
• 5- Tachycardia
• Incontinence

• Dysregulation of blood pressure

• Leukocytosis, and elevated creatine kinase.

• Fever is not an essential symptom and it can be
delayed.
• The syndrome begins abruptly while the patient is on
therapeutic, not toxic, dosages of medication.
• All the symptoms are fully manifest within 24 hours
and reach a maximum within 72 hours. ( 3-9 days of
tx)
• NMS can develop soon after the first dose or at any
time after prolonged treatment.
• Recovery usually occurs within 1 to several weeks, but
can be fatal in 20–30% of cases.
• The incidence of NMS is between 0.5% and 2.4%.

• Mortality rates have been reported as low as 4%

and as high as 20% (Bertorini, 1997).

• Pathophysiologic basis: dopaminergic

dysregulation and blockade of dopamine in the
basal ganglia and hypothalamus.
• All agents that block D2 receptors can induce
NMS, including :

• Risperidone

• Amisulpride

• Olanzapine and

• Phenothiazines with antihistaminic activity, such

as alimemazine
• A case of NMS associated with bupropion has
been reported (Kasantikul and Kanchanatawan,
2006)

• Tetrabenazine has been reported to cause NMS;

this seems likely to be due to its D2-blocking
activity (Reches et al., 1983)

• Reserpine has not been reported to cause NMS.

• Abrupt withdrawal of levodopa & dopamine

agonists.
• Risk factors for NMS:

• 1- Psychomotor excitement

• 2- Refusal of food

• 3- Weight loss

• 4- Oral administration of haloperidol at 15 mg/day

or above.

• 5- Young males appear to be more predisposed.

• Reports of an NMS-like syndrome following the
sudden withdrawal of:
• Amantadine

• Baclofen

• Combination of a long-acting neuroleptic and an

anticholinergic agent.
• The idiosyncratic nature and rarity of the
syndrome remain unexplained.

• TaqI A polymorphism of the dopamine D2 receptor

gene appears to occur more commonly in patients
who developed NMS.

• Kishida et al. (2004) found that patients with NMS

had a higher association with a polymorphism in
the D2 receptor gene.
• Treatment of NMS consists of discontinuing the
antipsychotic drugs and providing supportive
measures.

• Rapid relief of symptoms has been reported with the

use of dantrolene 3mg/kg-5mg/kg IV tds-qid,
bromocriptine 5mgqid, or levodopa.

• Nisijima and colleagues (1997) found levodopa to be

more effective than dantrolene.

• Tsujimoto and colleagues (1998) found intravenous

dantrolene plus hemodialysis to be effective.
• Subcutaneous apomorphine has been found to be
effective as a solo treatment (Wang and Hsieh,
2001)

• Gratz and Simpson (1994) recommended using

anticholinergics in an attempt to reverse rigidity
prior to utilizing bromocriptine.

• Carbamazepine was dramatically effective in two

patients (with recurrence on withdrawal of the
drug) (Thomas et al., 1998)
• Steroids added to standard therapy have been
reported to speed recovery time (Sato et al.,
2003).

• Re-exposure to dopamine receptor antagonists

does not necessarily lead to recurrence of NMS
(Singh and Albaranzanchi, 1995; Singh and
Hambidge, 1998).

• Residual catatonia that can last weeks to months

has been reported, with some patients responding
to ECT (Caroff et al., 2000).
• Hyponatremia can sometimes occur due to:

• 1- SIADH

• 2- Cerebral salt wasting syndrome

• Managed by salt replacement

• Other modalities :

• Benzodiazepines

• Amantadine, and

• Electroconvulsive therapy
 Tardive Syndromes

• Refers to a group of disorders that fit all of the

following essential criteria:
• 1- Abnormal involuntary movements or a sensation of
restlessness that often causes “unvoluntary”
movements
• 2- Exposure to at least one DRBA within 6 months of
the onset of symptoms (in exceptional cases, exposure
could be up to 12 months)
• 3- The disorder persists for at least 1 month after
stopping the offending drug(Fahn, 1984a; Stacy and
Jankovic, 1991)
Classic Tardive Dyskinesia

• Tardive dyskinesia, a hyperkinetic movement

disorder that causes choreic movements.

• Chorea is characterized by involuntary, rapid,

nonrepetitive, random, small-amplitude
movements that may be symmetric or asymmetric.
• Risk factors:

• Old age

• Certain predisposition of women

• Mental retardation & affective disorders

• History of substance abuse and

• Traumatic head injury

• Associated with chronic use, greater than 3
months, of dopaminergic blocking medications
including:

• Typical and atypical neuroleptic medications.

• Antiemetic agents: prochlorperazine and

metoclopramide.

• Except quetiapine and clozapine

• The tardive dyskinesia syndromes tend to persist and
can remain permanently.

• Can occur when the patient is taking these drugs or

within a period of time after stopping the drugs.

• Withdrawing the offending drugs often exacerbates the

severity of the movements because of removal of
dopamine receptor blockade.

• Increasing the dosage of these drugs often

ameliorates the movements because of increasing the
blockade.
• Most common is the pattern of repetitive, almost
rhythmic, movements that can be labeled as
stereotypic.

• This pattern often occurs in the oral-buccal-lingual (O-

B-L) region.

• Other parts of the body may also express rhythmic

movements, such as the hands, feet, and trunk (less
often).

• Respirations may also be affected with an altered

rhythmical pattern.
• TD is often accompanied by a feeling of inner
restlessness (akathisia): focal vs generalized.

• Focal akathisia is extremely uncomfortable and is

often expressed by the patient as a burning
sensation.

• Generalized akathisia is often accompanied by a

pattern of movement that appears to be executed
in an attempt to relieve the abnormal
uncomfortable sensations.
• The forehead and eyebrows are seldom involved
unless tardive dystonia is also present.

• Contrast to Huntington disease, in which chorea of

the forehead and eyebrows is more common than
choreic movements of the oral musculature.

• In TD, the mouth tends to show a pattern of

repetitive, complex chewing motions.
• Video dyskinesia
• The involuntary movements of the mouth in
classic TD are readily suppressed.

• Movements cease as the patient is putting food in

the mouth, when talking, or when a finger is
placed on the lips.

• the tongue tends to assume a continual writhing

motion of athetoid side-to-side and coiling
movements.
• Constant lingual movements might lead to tongue
hypertrophy, and macroglossia is a common
clinical sign.

• Tongue protrusion without darting back into the

mouth for more than half a minute is common.

• Contrast to chorea in Huntington’s disease, where

motor impersistence is common.
• Video OBL dyskinesia
 Pathophysiology of TD

• The biochemical basis of TD is still unclear.

• The explanation involving dopamine receptor
supersensitivity alone does not seem to be sufficient.
• Gerlach (1991) suggested that TD might be due to an
increased ratio of D1/D2 receptor activity.
• The typical neuroleptics block pre- and postsynaptic
D2 receptors, leaving D1 receptors spared.
• Thus, it is proposed that an increased D1 receptor
activation would lead to the dyskinesias.
• The effect of DRBAs on other interconnected
systems is suggested.

• Altered synaptic patterns between subsets of

dopaminergic neurons and other interconnected
neurons.

• Decreased GABA activity in the subthalamic

nucleus lend support to involvement of this
nucleus in TD.
• Oxyradicals have been implicated in the
pathogenetic mechanism for the tardive
syndromes (Lohr, 1991).

• DRBAs cause an increase in dopamine turnover,

resulting in an increased synthesis of hydrogen
peroxide.

• Hydrogen peroxide, if not rapidly metabolized, will

form oxyradicals, which can damage cell
membranes.
• Steen and colleagues (1997) reported that a
specific allelic variation of the dopamine D3
receptor (DRD3) gene is found at a higher
frequency (22–24%) of homozygosity
• A serine to glycine polymorphism in the first exon
of the DRD3 gene appears to be a risk factor for
developing TD (Liao et al., 2001, Ozdemir et al.,
2001).
• Polymorphisms in DRD3 have also been
associated with TD (Zai et al., 2009).
 Tardive Dystonia

• These movements are involuntary, repetitive, and

twisting.

• They may be intermittent or sustained and are

often painful.

• The dystonic movements are described by

location as focal, segmental, hemi-, or
generalized.
• Persistent dystonic movement as a complication
of DRBA therapy has long been noted (Druckman
et al., 1962)

• Has a different epidemiology and pharmacologic

response from those of classic tardive dyskinesia.

• Prevalence of tardive dystonia in chronic

psychiatric inpatients has been estimated to be
1.5–2% (Friedman et al., 1986; Yassa et al.,
1986).
• Occurs after prolonged use (ie, greater than 3
months) of dopamine blocking agents.

• Same medications that induces classic tardive

dyskinesia also triggers tardive dystonia.
• Focal tardive dystonias are usually cranial in
location.

• Affecting the jaw, tongue, and facial muscles.

• Tardive dystonia may also be accompanied by

tardive akathisia and by classic TD.

• Tardive dystonia can occur at all ages, whereas

classic TD is more common in the elderly.
• In primary dystonia, patients at younger age of
onset tend to develop generalized dystonia.
• Those with onset in adulthood are more likely to
have craniocervical focal or segmental dystonia.
• Regardless of age at onset, tardive dystonia
usually progresses over months or years from a
focal onset to become more widespread.
• Only 17% remain focal at the time of maximum
severity (Kiriakakis et al., 1998).
• Tardive dystonia in adults tends to remain focal or
segmental and tends to involve the craniocervical
region.

• The onset can be from days to years after

exposure to a DRBA.

• The range to extend from 4 days to 23 years of

exposure ( Kiriakakis and colleagues (1998).
• Men are significantly younger than women at
onset of dystonia.

• It develops after shorter exposure in men.

• Severe tardive dystonia was more common in

young men.

• Severe classic tardive dyskinesia was more

common in older women.
• Tardive dystonia tends to occur in all ages without
predilection for any particular age range.

• The mean age of onset in the literature is about 40

years.

• Idiopathic dystonia, shows a bimodal distribution

with one early peak in childhood and another later
peak in adulthood.
• Improvement with sensory tricks (geste
antagoniste) occurs both in idiopathic torsion
dystonia and tardive dystonia.

• Focal dystonias, such as tardive cervical dystonia,

tardive blepharospasm can resemble idiopathic
form.

• Retrocollis is more with tardive dystonia.

• A comparison of tardive and primary
oromandibular dystonia (OMD) showed :

• 1- Similar demographics

• 2- Both occurring predominantly in women

• 3- With jaw-closing dystonia being the most

common form (Tan and Jankovic, 2000).
• Primary OMD patients were more likely to have
coexistent cervical dystonia.

• Limb stereotypies, akathisia, and respiratory

dyskinesia were seen only in the tardive OMD.
• More characteristic of tardive dystonia:
• Retrocollis
• Trunk arching backward
• Internal rotation of the arms, extension of the elbows
and flexion of the wrists
• The presence of myoclonic movements in association
with dystonia.
• Reduction of dystonic movements with voluntary action
such as walking
• Video
• Patients with idiopathic dystonia more often have
lateral torticollis and twisting of the trunk laterally.

• The dystonic movements are usually exacerbated

by voluntary action.

• It can be severe enough to jeopardize patients by

causing life-threatening dysphagia.
• Video
 Tardive Akathisia

• The clinical phenomenology of tardive akathisia is

thought to be the same as that of acute akathisia.
• Moaning & focal pain are more common in tardive
akathisia than in acute akathisia.
• Mean age at onset of tardive akathisia was 58
years with a range from 21 to 82 years.
• The mean duration of dopamine receptor
antagonist exposure before the onset was 4.5
years with a range from 2 weeks to 22 years.
 Withdrawal Emergent
Syndrome
• First described in children who had been on
antipsychotic drugs for a long period of time and
then were withdrawn abruptly from their
medication (Polizos et al., 1973).

• The abnormal movements are brief and flow from

one muscle to another in a seemingly random
way.

• They differ from the movements of classic tardive

dyskinesia, which are brief, but stereotypical and
repetitive.
• Involve mainly the limbs, trunk, and neck, and
rarely the oral region, which is the most
prevalent site in classic tardive dyskinesia.

• The dyskinetic movements disappear

spontaneously within several weeks after
withdrawal of the DRBA.

• For immediate suppression of movements,

dopamine receptor antagonists can be reinstituted
and withdrawn gradually without recurrence of the
withdrawal emergent syndrome (Fahn, 1984a).
• A withdrawal reaction from melatonin with O-B-L
dyskinesia and akathisia was reported by Giladi
and Shabtai (1999)

• Withdrawal emergent syndrome is analogous to

the classic tardive dyskinesia seen in adults.

• Course is more benign and movements are more

generalized, resembling the choreic movements of
Sydenham disease.
• Video wes
 Treatment

• In classic tardive dyskinesia, prospective data show

33% remission in 2 years following elimination of the
DRBA (Kane et al., 1986).
• In retrospective studies, the remission rates were 12%
for tardive dystonia and 8% for tardive akathisia (Kang
et al., 1986; Burke et al., 1989).
• Younger age is associated with better chance of
remission. (Smith and Baldessarini, 1980)
• Earlier detection and discontinuation of dopamine
receptor antagonists were more favorable for
remission (Quitkin et al., 1977).
 Treatment of Classic
Tardive Dyskinesia
Pharmacological property Tetrabenazine Reserpine

Mechanism of action Selectively binds Binds hVMAT1 and

hVMAT2 hVMAT2
Reversibly binds Irreversibly binds
VMAT2 VMAT
Binds intravesicular Binds cytoplasmic site
site

Peripheral monoamine depletion No Yes

Duration of action in humans Short (approx. 12 Several days

hours)
Hypotension No Yes
Gastrointestinal effects No Yes
Dopamine receptor blocking activity Yes No
• Open-Label Extension of KINECT: A Phase 2
Study of Valbenazine (NBI-98854) for Tardive
Dyskinesia (S27.001)

• Mohammed Bari, Raj Shiwach, Roland Jimenez,

Scott Siegert, and Christopher O'Brien

• April 5, 2016, 86:16 Supplement S27.001;

published ahead of print April 8, 2015, 1526-632X
• Data from KINECT 2, a phase 2 randomized,
double-blind, placebo-controlled dose-
escalating trial in subjects (n=102) with
schizophrenia, schizoaffective disorder, mood
disorder or gastrointestinal (GI) disorder with
moderate or severe TD.

• The goal of the trial was to evaluate the safety

and efficacy of once-daily administered
valbenazine for TD.
• Valbenazine or placebo was administered once
daily for six weeks.
• All subjects randomized to valbenazine
received 25 mg through week two, at which
point the dose could be increased to 50 mg or
maintained.
• At week four, the dose could be increased to
75 mg, maintained, or reduced to the previous
dose.
• Participants who took the placebo capsule
also underwent similar, blinded dose
adjustments.
• Valbenazine was associated with a marked
reduction in the abnormal movements associated
with TD as assessed by the Abnormal Involuntary
Movement Scale (AIMS) and clinical global
impression of change (CGI-TD) score.
• The CGI-TD showed significant improvement with
treatment (67 percent versus 16 percent were
“much improved” or “very much improved.”
• AIMS scores improved by 2.6 points in the
valbenazine group versus a decrease of 0.2 points
in the placebo arm.
• KINECT 3: A Randomized, Double-Blind,
Placebo-Controlled Phase 3 Trial of
Valbenazine (NBI-98854) for Tardive
Dyskinesia (PL02.003)

• Robert Hauser6, Stewart Factor2,

Stephen Marder4, Mary Ann Knesevich5, Paul
Michael Ramirez1, Roland Jimenez3, Joshua
Burke3, Grace Liang3 and Christopher O'Brien3
• In the phase 3, KINECT 3 study, 234 patients with
moderate to severe neuroleptic-induced TD were
randomized to receive a once-daily dose of 80 mg
valbenazine, 40 mg valbenazine, or placebo, for six
weeks.
• The study's primary endpoint was a change from
baseline in the Abnormal Involuntary Movement
Scale (AIM) total dyskinesia score, as assessed by
blinded video raters.
• Safety was determined by adverse event (AE) rates
together with laboratory, electrocardiography, and
psychiatric assessments.
• Among the patients, 66 percent had
schizophrenia and 86 percent were receiving
stable doses of concomitant neuroleptics,
including 77 percent who were taking atypical
antipsychotic medication

• Valbenazine 80mg resulted in a significant

improvement in AIMS score vs. placebo (mean
change from baseline -3.2 vs. -0.1; p<0.0001).
The AIMS score was also reduced in the 40mg
group vs. placebo (mean change from baseline
-1.9 vs. -0.1; p=0.0021).
• Valbenazine was for the most part well tolerated,
with the frequency of adverse events similar in all
treatment groups and consistent with those of
prior studies.
• The most commonly reported adverse event was
somnolence, which occurred in 5 percent of
subjects in the 80 mg treatment cohort, 4 percent
in the 40 mg group, and 4 percent in the placebo
group.
• Three percent of subjects in the 40mg and placebo
groups discontinued treatment due to adverse
events, as did 4 percent in the 80 mg group.
• SD-809, or deutetrabenazine, was
granted breakthrough status by
the FDA last November.
• Atypical antipsychotics:

• Clozapine: upto 400 mg/day ( 50% response)

• Quetiapine: upto 600 mg/day

• Olanzapine

• Effect due to further D2 receptor blockade.

• Dopamine agonists:
• Activate the presynaptic dopamine receptors by using
low doses of a dopamine agonist.
• Which in turn would reduce the biosynthesis and
release of dopamine.
• Use of levodopa in an attempt to desensitize the
postsynaptic dopamine receptors.
• This can cause initial worsening of symptoms before
eventual improvement is expected after
discontinuation of levodopa.
• Dopaminergic drugs can also lead to overt recurrence
of underlying psychosis.

• This approach has theoretical merit, but not carried

out.

• Amantadine has been reported to have some benefit,

mostly due to its glutamate receptor blocking effect
rather than its dopaminergic effect.
• Nondopaminergic medications:
• Clonazepam
• Propranolol, fusaric acid, and clonidine
• Anticholinergics, pyridoxine, tryptophan,
cyproheptadine, vasopressin, naloxone, morphine,
and estrogen were reported to be of no benefit.
• Pyridoxine was found to reduce the severity of TD
(Lerner et al., 2001).
• Buspirone has been reported to be beneficial
(Moss et al., 1993)
• Calcium channel blockers have been reported to
reduce the severity of tardive dyskinesia (Kushnir
and Ratner, 1989
• A combination of acetazolamide and thiamine was
found to reduce both TD and drug-induced
parkinsonism (Cowen et al., 1997)
• Lithium
• Meta-analysis showed that baclofen, deanol, and
diazepam were no more effective than a placebo.

• Meta-analysis found that five interventions were

effective: levodopa, oxypertine, sodium valproate,
tiapride and vitamin E.

• Data from single randomized clinical trials

revealed that insulin, α-methyldopa, and reserpine
were more effective than a placebo.
• Treatment with vitamin E has been found to
reduce the severity of tardive dyskinesia (Elkashef
et al., 1990

• There continue to be reports of TD responding to

open-label trials. Gabapentin, pyridoxine,
branched amino acids.

• Levetiracetam was helpful in a small trial

(Konitsiotis et al., 2006).
• Injections of botulinum toxin into the muscles
causing oral dyskinesia have been reported to be
effective in reducing the movements (Rapaport et
al., 2000).

• Sporadic reports noted efficacy of

electroconvulsive therapy in refractory cases of
TD (Price and Levin, 1978)
 Treatment of Tardive
Dystonia
• The most effective medications for tardive
dystonia are also antidopaminergic drugs (Kang et
al., 1986)

• Reserpine and TBZ each produce improvement in

about 50% of patients.

• DRBAs are more effective in suppressing the

movements (77%).

• The atypical antipsychotic clozapine has been

helpful in some patients with tardive dystonia.
• There are reports of quetiapine’s effectiveness as
well (Gourzis et al., 2005).
• Combination of clozapine and clonazepam has
been effective in some patients (Shapleske et al.,
1996).
• Antimuscarinics are almost as effective as
antidopaminergic drugs.
• This is different from classic tardive dyskinesia,
which may get worse with antimuscarinics (Yassa,
1988).
• Improvement rate ( 46 % ) on antimuscarinics
such as trihexyphenidyl and ethopropazine.

• Benzodiazepines are mainly helpful as adjunctive

therapy with dopamine-depleting or anticholinergic
drugs.

• Minimal success with propranolol, levodopa,

carbamazepine, and baclofen has been noted.
• Bromocriptine, deanol, clonidine, lisuride, amantadine,
and valproate were reported with mixed results.

• Verapamil was reported to be effective in one patient

(Abad and Ovsiew, 1993)

• Opioids do not have lasting value in suppressing

tardive dystonia (Berg et al., 2001)

• One study found the combination of naltrexone and

clonazepam to offer some benefit (Wonodi et al.,
2004b).
• Botulinum toxin injection into the affected parts might
be helpful.
• Electroconvulsive therapy (ECT) might be effective in
intractable cases (Yoshida et al., 1996)
• Deep brain stimulation in the globus pallidus interna is
often effective (Franzini et al., 2005)
• Deep brain stimulation in the pallidum can be safe and
effective (Capelle et al., 2010; Chang et al., 2010)
• Intrathecal baclofen (Dressler et al., 1997)
 Treatment of Tardive
Akathisia
• Tardive akathisia is difficult to treat and does not
respond to anticholinergics, which have been
reported to help acute akathisia.
• Patients improved on reserpine up to 5 mg/day
(87%) and 58% on TBZ up to 175 mg/day.
• Opioids were reported to be beneficial (Walters et
al., 1986) but the effect has not been persistent.
• ECT can be effective in refractory cases (Hermesh
et al., 1992).
 Treatment Summary

• Taper and slowly eliminate causative agents if clinically

possible.
• Avoid sudden cessation of these drugs.
• Avoid drugs, if possible (i.e., wait for spontaneous
recovery).
• If necessary to treat the symptoms, first use dopamine
depleting drugs.
• Consider melatonin on the basis of one report (Shamir
et al., 2001).
• Consider the true atypical antipsychotic agents,
clozapine and quetiapine.

• If these fail, consider tiny doses of a dopamine

receptor agonist to activate only the presynaptic
dopamine receptor and reduce the biosynthesis of
dopamine.

• For tardive dystonia, consider antimuscarinics.

• For intractable tardive akathisia, consider ECT

• Typical antipsychotic agents can be used when all
fails.

• Combining this with a dopamine depletor may:

• 1- Increase the potency of the antidyskinetic

effect.

• 2- Protect against a worsening of the underlying

tardive pathology.
• Thalamotomy, pallidotomy, and deep brain
stimulation of the thalamus and pallidum have
been performed for tardive dystonia with success.

• DBS-Gpi appears to be the preferred surgical

procedure if the symptoms remain severe and all
medication trials fail.
 DRUG-INDUCED TREMOR

• A rhythmic, involuntary, oscillatory movement of

any body part and is named for the position of
great- est prominence.

• Typically begin shortly after institution of the

offending medication.

• May be postural, rest, or intention.

• The most common form is the enhanced physi-

ologic tremor.
• Elimination of the offending medication often
ameliorates drug-induced tremor.
• If the offending agent cannot be discontinued:
• Propanolol up to 240 mg a day and
• Primidone up to 250 mg a day, and benzodiazepines
such as clonazepam.
 DRUG-INDUCED
MYOCLONUS

• An involuntary ( jerky-lightning) hyperkinetic

movement disorder.

• Classified as either positive or negative.

• Positive myoclonus: sudden brief muscular

contractions.

• Negative myoclonus involves pauses in muscular

activity.
• Pathophysiologic mechanism :

• Enhancement of serotonin and g-amino- butyric

acid GABA.

• The best therapy for drug-induced myoclonus is

identification and elimination of the offending
agent.
 DRUG-INDUCED TICS

• A hyperkinetic movement disorder consisting of :

• Repetitive, stereotyped motor or vocal movements

that may be simple or complex.

• An urge to perform the movement.

• Relief after performing the movement.

• Some ability to suppress the movement for short

amounts of time.
• Tics have a predilection for cranial and cervical
musculature but may occur in any body location.

• Caused by enhanced dopamine levels

• Associated with multiple drugs including:

• Methylphenidate, dextroamphetamine, pemoline,

cocaine, and, lamotrigine.

• Tx: eliminate the drug.

 Conclusion

• Drug-induced movement disorders can be commonly

seen in outpatient and inpatient clinical practice.
• Take a thorough past and present medication history.
• Any recently added medications or changes in
dosages.
• The best therapy for treating a drug-induced
movement disorder is elimination of the offending
agent.
• If elimination is not possible due to underlying illness,
then attempting to decrease the dosage or change to a
less-offensive agent.
• If all of the above measures are impossible or a
tardive syndrome exists, then medical therapy can
be considered.

• The choice of therapeutic agent is guided by:

• 1- Type of movement disorder.

• 2- Coexistent medical problems and medications.

 Thank you
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