Medication Induced

Movement Disorders

Dr Prerna Khar
Dr Jitendra Dongre
Guide: Dr Ajit Naik
Moderator: Dr Niteen Abhivant
 TOPICS TO BE COVERED

• Introduction
• Classification
• Pathophysiology
• Types of Movement Disorders
• Management
• DSM diagnostic categories
• Scales
• Medication Induced Tremors
• Clinical Approach and Practical Tips
 INTRODUCTION

• Medication-induced movement disorder (Extra-

Pyramidal Side Effects, EPSE) occurs due to
treatment with antipsychotic medications.
• Though they are commonly caused by the typical
antipsychotics, but can also be caused by the atypical.
 IMPLICATIONS

• The movement disorders associated with antipsychotics are

disabling and distressing and result in behavioral
disturbances(violence and aggression), non-adherence,and
exacerbation of psychosis.
• Some of the motor signs may be misinterpreted as psychotic
symptoms.
• The bradykinesia, limb stiffness, and mask-like facies seen in
Parkinsonism are a social and functional handicap.
• The restlessness and agitation associated with akathisia have
similar effects.
CLASSIFICATION
 PATHOPHYSIOLOGY

• Though the pathophysiology of MIMD has not been clearly

elucidated yet, but certain theories and hypothesis suggest the
interplay between:
– genetic predisposition,
– dopaminergic system hypersensitivity in the basal ganglia,
– decreased functional reserve, and
– over activation of the cholinergic system.
RISK FACTORS
1.Dystonia

OPISTHOTONUS

OCULOGYRIC CRISIS
 Dystonia Contd..
• Signs And Symptoms
-Occulogyric Crisis
-Torticollis
-Inability to swallow or speak freely(Glossopharyngeal spasm)
-Opisthotonus/jaw dislocation
-Segmental -involve two or more contiguous regions.
Meige’s syndrome: blepharospasm + oromandibular dystonia
-Multifocal :two or more non-contiguous regions
-Hemidystonia:one side of the body (e.g., ipsilateral arm and leg).
-Generalized -widespread, involving both legs and at least one other body region
 Dystonia Contd..

• Mechanism:.
• Acute saturation of D2 receptors
• Preclinical studies :sigma-1 and sigma-2 receptors.
- Motor regions of the brain
-Involved in the control of posture and movement
• Interference with presynaptic dopamine receptors
• Mismatch between excess release of dopamine and
coincident hypersensitivity of dopamine receptors.
- Overactivation of unblocked D1 receptors
 Dystonia Contd..

• Prevelance: Approx 10%

More common in-:Young males
Neuroleptic Naïve
High potency drugs
Rare in elderly.
Recent use of cocaine
• Time Taken To Develop:
- Acute: Hours of starting AP (mins if IM)
- Tardive Dsytonia: Months to years.
 Dystonia Contd..
• Treatment:
- Anticholinergic drugs ( Trihexyphenydyl)
- If Unable to swallow/ acute- IM (20 mins) or IV (5mins)
- Switch to antipsychotic with lower propensity to cause EPS.
- Baclofen:5 mg/day Increasing by 5 mg/day every 3 – 5 days .
Intrathecal doses, if with LL spasticity
- Tardive dystonia may respond to ECT.
- Botulinum toxin: If above fail.
- rTMS (Repetitive Transcranial Magnetic Stimulation)
- Occupational therapy
• *Cloud L et al.Treatment strategies for dystonia. Expert Opin Pharmacother. 2010 January ;
11(1): 5–15. doi:10.1517/14656560903426171. NIH public access
 2.Pseudoparkinsonism

• Signs & Symptoms:

-Tremor/Rigidity.
-Bradykinesia
- Bradyphrenia(slowed thinking)
- Salivation
The above can be mistaken for depression/ negative symptoms of
Schizophrenia
Pseudoparkinsonism Contd…
 Pseudoparkinsonism Contd…

PSEUDOPARKINSONISM PARKINSON’S DISEASE

Apraxic Slowness Bradykinesia

Essential tremor, myoclonus Resting tremor

Paratonic rigidity Lead pipe rigidity

Slow, shuffling apraxic gait Slow, shuffling gait with

festination, retropulsion
 Pseudoparkinsonism Contd…

• Rating Scales: Simpson Angus EPS Rating Scale.

• Prevalence: -20%
MC in: -Elderly Females
-Pre-existing Neurological Damage
• Time Taken To Develop: Days to weeks after starting
AP/ if dose is increased.
 Pseudoparkinsonism Contd…

• Treatment:
- Decrease the dose of AP
- Prescribe anti-cholinergic. Review use every 3 months -most
don’t require long term
1. Benztropine (Cogentin) : 2-8 mg
2.Trihexyphenidyl :6-10 mg;
3.Diphenhydramine hydrochloride (Benadryl):25 -100
mg
- Change to AP with lower propensity to cause EPS.
 3.Akathisia (Restlessness)

• Signs & Symptoms:

- Foot stomping when seated.
- Crossing/uncrossing legs.
- Pacing up and down.
• Rating Scale: Barnes Akathesia Rating Scale
-Hillside akathesia rating scale
-Prince Henry Hospital akathesia scale
• Prevalence: 25%
-Less with SGAs
-Aripirazole> Lurasidone> Risperidone>, Olanzapine>,
Quetiapine> Clozapine
 Types

• Acute :within weeks < 6 months.

-Dysphoria & inner sense of restlessness.
• Chronic :> 6 months
-After the introduction of/ change in medication
-Stereotypic movements + presence of limb or orofacial
dyskinesias.
• Tardive : Often associated with tardive dyskinesia
-delayed onset
- May persist even after medication cessation.
• Withdrawal:Within 6 weeks of switching or stopping an AP/
anticholinergic agent
 Akathesia Contd…

• Pseudoakathesia:
• In a relatively small number of people, repetitive restless
movements characteristic of akathisia may not be
accompanied by any sense of inner restlessness or compulsion
to move.
• More common in male and older patients.
• May coexist with negative symptoms and tardive dyskinesia
 Akathisia Contd…
• Mechanism:
-Due to dopamine receptor blockade in brain areas other than the striatum.
-When akathisia occurs alone in the absence of Parkinsonian symptoms, it
may be due to dopaminergic blockade in the mesocortical tract rather than
in the nigrostriatal pathway.
 Akathisia Contd…
• Time Taken To Develop:
- Hours to weeks after starting.
- Increasing the dose.
- Tardive Akathesia-longer to develop, can last even after
withdrawing the AP
• Treatment
- Decrease the dose.
- Change to AP with lower propensity.
- Propranolol:30-80 mg/day
- Low dose clonazepam
- Anticholinergics are generally not helpful
Treatment Algorithm for Akathesia
 4.Tardive Dyskinesia

• Signs & Symptoms:

-Grimacing
-Tongue protrusion (fly catching)
-Lip smacking/ chewing
- Pressing lip against the cheek (Bonbon sign)
-Choreiform hand movements(pill rolling/ paino playing)
-Rapid eye/leg movements.
-Severe movements-difficulty in speaking /eating /breathing.
- Irregular breathing, belching, grunting sounds whistling,sucking.
D/D:Rabbit syndrome
Tardive Dyskinesia Contd…
 Tardive Dyskinesia Contd…

• Pathogenesis:
• -Dopamine Receptor Supersensitivity
Chronic DA blockade leads to super sensitivity of postsynaptic
DA receptors. (upregulation)
• GABA insufficiency Hypothesis
Decreased activity of striatal GABA neurons, and reduced GABA
turnover and increase GABA receptors.
• Neurodegenerative Hypothesis
Caused due to generation of free radicals and excititoxicity,
particularly in the striatum
 Cholinergic Degeneration
Due to overactivation of cholinergic neurons in the striatum when
released from Dopaminergic inhibition after antipsychotics are
administered.
 Tardive Dyskinesia Contd…

• Increased proliferation of D2 receptors in certain parts of the

striatum
• Neuroleptic accumulation in neuromelanin cells with nigral
damage
• Oxidative stress – free radical production with chronic
neuroleptic use
• Altered corticostriatal input, cortical damage
• Related to neurobiology of schizophrenia itself
• Endocrine factors (oestrogen in women)
• Polymorphisms -DA2 receptor, DA3 receptor, dopamine
transporter (DAT1), & 5HT 2A receptor genes.
 Tardive Dyskinesia Contd…

• Rating Scales: AIMS (Abnormal Involuntary Movement Scale)

• Prevalence: 5% of pts/ yr of AP exposure.
MC in : Elderly women
-Those with affective illness.
-EPS in early phase of T/T.
-Total Neuroleptic load, typical, injectables, intermittent
treatment
-Negative schizophrenia
-Diabetes mellitus, Smoking, Alcohol
• Anticholinergic medications worsen the TD or make the latent TD
manifest.
 Tardive Dyskinesia Contd…

Can be a/w neurocognitive defecits.

• Time Taken To Develop: Months to years.
• TD is a/w greater mortality, severe psychopathology.
• Can occur after smaller doses of convential drugs/ drug naïve
pts
 Differential Diagnosis

• Wilson’s disease • Basal ganglia calcification

• Huntington’s chorea • Other drugs
• Syndenham’s chorea • Hepatic encephalopathy
• Neuroacanthocytosis • Senile chorea
• Hallervorden-Spartz disease • Multiple sclerosis
• SLE • Acute intermittent porphyria
• Encephalitis • Ataxia telangiectasia
• Toxins (Hg, CO)
• Early onset chorea
 Tardive Dyskinesia Contd…

• Treatment:
-Stop anticholinergic if prescribed.(controversial)
- Reduce dose of AP(can initially worsen TD)
- Change to AP with lower propensity.
- Clozapine-Resolution of symptoms/ Quetiapine.
- Tetrabenazine(licensed only in UK) (DA depletor) 25-
200mg/day
- Ginkgo Biloba
- Vitamin E (400-600 IU/ day)
- BZD (reduce the anxiety associated with it)
 Tardive Dyskinesia Contd…

• Preventive Measures:
• -Frequently assess the need for continuation of antipsychotic,
especially if affective illness or dementia is diagnosed
• Continuous versus intermittent treatment
• Lowest effective dose
• Avoiding older high-potency agents
• Administration of AIMS at 6-monthly intervals if on typicals
and 12-monthly intervals on atypicals (3 and 6-monthly,
respectively, if at high risk.)
• Preferable use of atypicals, especially olanzapine or risperidone
at <6 mg/d (Glazer, 2000)
 APA Task Force Recommendations (1997,
2004)

• Establish objective evidence that antipsychotics are effective

for an individual
• Using the lowest effective dose
• Cautious use in children, the elderly and in mood disorders
• Regular examination of patients for TD
• Consider alternatives, obtain informed consent, and consider
dosage reduction if TD present
• If worsening, consider (a) stopping the drug, (b) change to
another drug, (c) clozapine
 APA guidelines

 IF AIMS Score is <2

1. If TD is stable – no treatment, follow-up with AIMS
scores as per guidelines.
2. If TD is unstable or causing distress
 If patient does not need an antipsychotic – taper and
stop
 If patient needs an antipsychotic
a. If on typicals – change to atypicals
b. If on atypicals – change to clozapine
 If AIMS score > 2 – tardive dyskinesia consultation
1. If TD can be managed clinically – start clozapine; if
tolerated, continue; if not tolerated, try other anti-
dyskinetics
2. If other anti-dyskinetics also do not work – referral
to specialized movement disorders program

Regular follow-up and AIMS administration

is of paramount importance.
 5.Withdrawal Emergent Dyskinesia

• Generalized chorea, athetosis,  tongue protrusion, chewing

movements, facial grimacing, finger, toe, ankle movements,
ballistic movements, vocalizations, and spasmodic torticollis.
• The movements worsen with increasing level of arousal or
anxiety.
• The most widely accepted theory is that of dopaminergic
hypersensitivity.
• Usually time-limiting-lasting 4-8 wks. (if persists-TD)
• Treatment: Re-assurance  that withdrawal dyskinesia usually
disappears within a few weeks. If symptoms are distressing
then restart therapy and slow down titration.
 OTHER MEDICATIONS CAUSING
MOVEMENT DISORDERS

• Antiemetics like Domperidone, Metoclopramide.

• Antidepressant- amoxapine.
• Valproate and Lithium- hand tremors. (medication induced
postural tremor.)
 DSM 5 Diagnostic Categories Of
Medication Induced Movement
Disorders
• Neuroleptic Induced Parkinsonism.
• Other Medication induced Parkinsonism.
• Medication induced acute Dystonia
• Medication induced Acute Akathesia.
• Tardive Dyskinesia.
• Tardive Dystonia
• Tardive Akathisia
• Medication induced Postural tremor.
Abnormal involuntary movement scale
(AIMS)
• The AIMS is used to detect TD and to follow the
severity of a patients TD overtime
• 12 item anchored scale
• -item 1-10 are rated on a 5 point anchored scale
 Items 1-4 assess the oro-facial movements
 Items 5-7 deals with truncal and extremity dyskinesia
 Item 8-10 deal with global severity as judged by
examiner, and patients awareness and distressed
associated with them
 Items 11-12 are yes-no questions concerning problem
with teeth and/or dentures
Scoring
• A total score of 1-7 (categories 1,2,3) can be
calculated. These represent observed movements
• Item 8 can be used as an overall severity index
• Item 9(incapacitation) and 10(awareness) provide
additional information
• Item 11 dental status and 12 dentures provides
information that may be useful in determining lip,
jaw and tongue movements
SIMPSON-ANGUS EXTRAPYRAMIDAL SIDE EFFECTS SCALE
 Barnes Akathisia Rating Scale (BARS)

• Name:________________________________________ Date:__________________

Objective
• 0 Normal, occasional fidgety movements of the limbs
• 1 Presence of characteristic restless movements: shuffling or
tramping movements of the legs/feet, or
swinging of one leg while sitting, and/or rocking from foot to
foot or “walking on the spot” when standing, but movements
present for less than half the time observed
• 2 Observed phenomena, as described in (1) above, which are
present for at least half the observation period
• 3 Patient is constantly engaged in characteristic restless
movements, and/or has the inability to remain seated or
standing without walking or pacing, during the time observed
Subjective
• Awareness of restlessness
0 Absence of inner restlessness
1 Non-specific sense of inner restlessness
2 The patient is aware of an inability to keep the legs still, or a
desire to move the legs, and/or complains of inner restlessness
aggravated specifically by being required to stand still
3 Awareness of intense compulsion to move most of the time
and/or reports strong desire to walk or pace most of the time
Distress related to restlessness
0 No distress
1 Mild
2 Moderate
3 Severe
Scoring the Barnes Akathisia Rating Scale (BARS)
The Barnes Akathisia Rating Scale is scored as
follows:
• Objective Akathisia, Subjective Awareness of
Restlessness and Subjective Distress
• Related to Restlessness are rated on a 4-point
scale from 0 – 3 and are summed yielding a total
score ranging from 0 to 9.
• The Global Clinical Assessment of Akathisia uses a
5-point scale ranging from 0 – 4.
 Recently FDA approved first drug to treat
Tardive dyskinesia- : VALBENAZINE

• Ingrezza (Valbenazine)
• FDA approved: Yes (First approved April 11th,
2017)
• Brand name: Ingrezza
• Generic name: valbenazine
• Dosage form: Capsules
• Treatment for: Tardive Dyskinesia
 About Valbenazine

• Highly-selective VMAT2 inhibitor that modulates

dopamine release during nerve communication,
showing little or no affinity for VMAT1, other
receptors, transporters and ion channels.
• Valbenazine is a prodrug which is an ester of [+]-
α-dihydrotetrabenazine (DTBZ) with the amino
acid L-valine
• It is extensively hydrolyzed to the active
metabolite DTBZ
• Plasma protein binding of valbenazine is over
99%, and that of DTBZ is about 64%.
The biological half-life of both valbenazine and
DTBZ is 15 to 22 hours.
• Liver enzymes involved in inactivation are
CYP3A4, CYP3A5 and CYP2D6.
• The drug is excreted, mostly in form of
inactive metabolites, via the urine (60%) and
the feces (30%)
Dosages: once daily dosing
- Start with 40 mg capsule for one week, after one week 80mg.
WARNINGS & PRECAUTIONS
- Somnolence
- INGREZZA can cause somnolence. Patients should not perform
activities requiring mental alertness such as operating a motor
vehicle or operating hazardous machinery until they know how
they will be affected by INGREZZA.
- QT Prolongation

ADVERSE REACTIONS
• The most common adverse reaction is somnolence. Other adverse
reactions include: anticholinergic effects, balance disorders/falls,
headache, akathisia, vomiting, nausea, and arthralgia.
 REFERENCES

• Maudsley Prescriber’s guide 4th edition.

• Antipsychotic-Induced Movement Disorders: Evaluation and Treatment: Dr
Maju Matheww, Psychiatry 2005.
• CTP: 10th edition. Medication Induced Movement Disorders.
• Pseudoparkinsonism: A review of a common nonparkinsonian hypokinetic
movement disorder :Kurlan et al. Advances in Parkinson’s Disease. Vol.2,
No.4, 108-112 (2013)
• Perminder S. Sachdev .Neuroleptic-induced Movement Disorders: An
Overview. Psychiatr Clin N Am 28 (2005) 255–274
• DSM 5
• Cloud L et al.Treatment strategies for dystonia. Expert Opin Pharmacother.
2010 January ; 11(1): 5–15. doi:10.1517/14656560903426171. NIH public
access
THANK YOU
 Tremors

 Tremor: series of involuntary, relatively rhythmic, purposeless,

oscillatory movements due to intermittent muscle contractions
 Simple tremor involves only a single muscle group
 Compound tremor involves several muscle groups

 -several elements in combination

 -resulting in a series of complex movements
 may be unilateral or bilateral
 most commonly involves distal parts of the extremities

 -fingers or hands
 may also affect the arms, feet, legs, tongue, eyelids, jaw, and head
 may occasionally involve the entire body
• Rate may be slow, medium, or fast
• Slow: Oscillations of 3 to 5 Hz
• Rapid: Oscillations of 10 to 20 Hz
• Amplitude may be fine, coarse, or medium
• The relationship to rest or activity is the basis for classification into
two primary tremor types:
• -resting
• -action
• RESTING (static) tremors are present mainly during relaxation (e.g.,
with the hands in the lap)
• Attenuate when the part is used
• Rest tremor is seen primarily in PD and other parkinsonian
syndromes
• ACTION TREMORS are divided into subtypes:
• postural
• kinetic
• task-specific
Postural:
• Postural tremors become evident when the limbs are
maintained in an antigravity position (e.g., arms
outstretched)
Types of postural tremor:
-enhanced physiologic tremor
-essential tremor (ET)
Kinetic tremor:
• Appears when making a voluntary movement
• May occur at the beginning, during or at the end of the movement
• Example : intention (terminal) tremor
• Intention tremor is a form of action tremor seen primarily in cerebellar
disease.
• Intention tremor: appears when precision is required to touch a target,
as in finger-nose-finger or toe-to-finger test
• Progressively worsens during the movement
• Approaching the target causes
-the limb to shake,
-side-to-side perpendicular to the line of travel,
-amplitude of the oscillation increases toward the end
• Tremors are accentuated by emotional excitement
• Many normal individuals develop tremor with anxiety,
apprehension, and fatigue
• Physiologic tremor : is present in normal individuals
• frequency varies from 8 to 12 Hz
• Can occur normal persons by anxiety, fright, fatigue
(rock climber's tremor)
• In conditions with increased adrenergic activity
 Essential Tremor

• Often familial
• ET may be a form of enhanced physiological tremor
• Prevalence of ET increases with age
• First appear anywhere between the second and sixth
decades of life
• Tends to be slowly progressive
• ET is a postural and action tremor, that tends to affect
the hands, head, and voice
• Made worse by anxiety
• Senile tremor is ET occurring during senescence with
a negative family history