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Extrapyramidal Symptoms
Tardive Dyskinesia

Causes of Extrapyramidal Symptoms

Extrapyramidal Symptoms - Neurologic symptoms caused by antipsychotic
medications due to their influence on the dopaminergic pathways
Dopamine receptor blocking agents:

Typical/1st-Generation Antipsychotics - blocks D2 receptors

Atypical/2nd-Generation Antipsychotics - blocks D2 and/or 5HT-2A receptors
Some Antiemetics
Some Antidepressants

Typical antipsychotics > Atypical Antipsychotics (lower D2 or higher 5HT-2A) - some

research has shown that atypical are just as likely to cause EPS

High-Potency Typical Antipsychotics (more EPS & less
histaminic, alpha-adrenergic, and anticholinergic effects):

Haloperidol (Haldol)

Fluphenazine (Prolixin)
Low-Potency Typical Antipsychotics (fewer EPS but more
histaminic, alpha-adrenergic, and anticholinergic effects):

Chlorpromazine (Thorazine/Largactil) (may cause corneal


Thioridazine (Mellaril) (may cause retinitis pigmentosa)

Mesoridazine (Serentil)


Metoclopramide (Reglan)

Prochlorperazine (Compro)

Atypical Antipsychotics:

Risperidone (Risperdol)

Paliperidone (Invega)

Clozapine (Clozaril)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Aripiprazole (Abilify)

Lurasidone (Latuda) (only antipsychotic in

Pregnancy Category B)


Duloxetine (Cymbalta)

Sertraline (Zoloft)

Escitalopram (Lexapro)

Fluoxetine (Prozac)

Bupropion (Welbutrin)

Dopaminergic Pathways
Mesolimbic Pathway - aka reward pathway; thought to play a
central role in addiction and implicated in schizophrenia (positive
symptoms > negative symptoms) and depression
Mesocortical Pathway - thought to be involved with cognitive
control, motivation, and emotional response; implicated in
schizophrenia and thought to be associated with the negative
symptoms of the disease
Nigrostriatal Pathway - involved with movement; particularly
with initiating movement**
Tuberoinfundibular Pathway - influences secretion of certain
hormones (particularly prolactin)

Pathophysiology of EPS
Requires blockade of 65% mesolimbic dopamine receptors and 80%
nigrostriatal dopamine receptors
Clozapine and quetiapine have lowest risk; haloperidol has highest
Quetiapine preferred because of agranulocytosis risk of clozapine
Risperidone has highest risk out of the atypicals
Rapid dissociation from receptors is important for decreased potential of EPS
Serotonin believed to enhance dopamine release to decrease EPS potential

Prevalence of EPS
Study of chronic institutionalized patients with schizophrenia
Typical neuroleptics caused movement disorders in 61.6% of patients
31.3% had akathisia
23.3% had parkinsonism
32.3% had tardive dyskinesia
Older females at risk of tardive dyskinesia
Young males at risk of dystonia
Elderly are prone to drug-induced parkinsonism

Extrapyramidal Effects Timeline

Acute dystonia - 4 days
- (Hours to Days)
Akathisia - 4 days
- (Days to Weeks)
Parkinsonism - 4 weeks
- (Days to Weeks)
Tardive Dyskinesia - 4 months
- (Months to Years)

Acute Dystonia - Epidemiology & Pathophysiology

Acute Dystonia - brief, often painful muscle contractions, usually characterized
by twisting and abnormal postures
2-94% of patients on typical neuroleptics
Greatest risk within first week of treatment
Pathophysiology - dopaminergic hypofunction within basal ganglia (caused by
the dopamine blocking agents) and overactivity of cholinergic system
Higher frequency with antipsychotics of higher potency- (haloperidol) as
opposed to lower potency antipsychotics (chlorpromazine)

Acute Dystonia - Clinical Features

Onset - within hours to days
Classical Presentation - 3 Os:

Oculogyric crisis - conjugate deviation of the

eyes (usually upward or laterally)
Opisthotonos (involuntary posturing of head,
neck, or spine backwards)
Oromandibular dystonia (difficulty opening or
closing the jaw)

Acute Dystonia - Clinical Features

Blepharospasm (involuntary eyelid closure)
Trismus (jaw-closing dystonia)
Laryngeal spasm
Tongue Protrusion
Respiratory Stridor
Symptoms may interfere with ambulation, breathing, speaking, swallowing, or
Rhabdomyolysis may occur for extended muscle contractures

Acute Dystonia - Clinical Features

Possible noncompliance with medications or
exacerbation of current symptoms
Tardive Dystonia - chronic dystonia months to years
after treatment, normally with tardive dyskinesia
Pisa Syndrome (aka Pleurothotonus) - rare form of
dystonia that is characterized by sustained truncal
Presence of fever, rigidity, altered level of
consciousness, autonomic instability - rule out
neuroleptic malignant syndrome

Acute Dystonia - Risk Factors

Young age
Mental retardation
Use of high potency neuroleptics
Presence of Tardive Dyskinesia

Acute Dystonia - Morbidity and Mortality

Acute dystonia resolves with reduction or removal of dose
Laryngeal spasm in severe cases may be life threatening
Status Dystonicus - rare with tardive dystonia, rhabdomyolysis,
myoglobinuria, and renal failure; rare
Remission from tardive dystonia is uncommon

Acute Dystonia - Therapeutic Management

Acute dystonic reactions need to be treated urgently (sometimes emergently)
Antimuscarinics - Benztropine (Cogentin), diphenhydramine (Benadryl),
trihexyphenidyl (PO, IM, IV)

Reduce rate of dystonia twofold, 5-11 fold with typical antipsychotics

Continue using afterwards or decreasing dose of antipsychotic

Efficacy of prophylaxis is inversely related to the age of the patient

Tardive dystonia - less consistently treated, can use local injections of

Dystonia Video

Akathisia - Epidemiology and Pathophysiology

Akathisia - subjective feeling of generalized restlessness characterized by the
inability to relax, anxiety, pacing, compelling need to move, etc.
20-30% chance for acute akathisia and 30% chance for tardive akathisia
2-3 times lower with atypical antipsychotics
Possible to get from SSRIs (at initiation or discontinuation)
Dopamine/serotonin imbalance within cortical and subcortical areas

Akathisia - Clinical Features

Restlessness (usually of the legs) with at least one of the following:

Fidgety movements or leg swinging while seated

Marching on the spot while standing

Rocking from one foot to another

Pacing back and forth

Inability to sit or stand still for several minutes

Akathisia - Clinical Features

Movements are voluntary and are a reaction to the restlessness
Symptoms may also start after withdrawal of drugs
Withdrawal of anti-akathisia drug may unmask the akathisia
Tardive akathisia starts after 3 months of initiation
Symptoms improve after lying down

Akathisia - Risk Factors

Advanced age
Cognitive impairment
High potency/dose neuroleptic
Iron deficiency
Mental Retardation
Negative symptoms of schizophrenia
Rapid neuroleptic dose escalation

Akathisia - Therapeutic Management

Prevention is key
Discontinue causative agent or switch to another agent
Administration of -blocker such as propranolol can help, 2 receptor blocker
is necessary
Anti-muscarinics, benzodiazepines, or anti-serotonergic (cyproheptadine)
agents can be used as well
Iron supplementation is controversial

Parkinsonism - Epidemiology and Pathophysiology

Parkinsonism - clinical syndrome characterized by tremor, bradykinesia,
rigidity, and postural instability; a symptom complex
Second most common form of parkinsonism (first is Parkinsons)
Antipsychotics cause 70-80% of drug induced parkinsonism

20-66% of patients on neuroleptics

Dopamine receptors in the Nigrostriatal pathway, which influence movement

initiation, are affected to cause Parkinsonism symptoms

Parkinsonism - Clinical Features

Indistinguishable from idiopathic parkinsonism
Contains two of the following symptoms:

Tremors (rest or postural; classical pill-rolling); most common

Rigidity (classic cogwheel rigidity)

Other symptoms include reduced facial expression (flat affect), reduced

energy and motivation, drooling, shuffling, and rabbit syndrome (tremors of
lips and perioral muscles)

Parkinsonism - Risk Factors

Advanced age

Parkinsonism - Morbidity and Mortality

Persistent parkinsonism is possible even after management (such as stopping
causative agent)
Reduced quality of life
Watch out for depression!

Parkinsonism - Therapeutic Management

Dose reduction
Switch from typical to atypical antipsychotic may help
Antimuscarinic agents are used in younger patients (what is one?)
Amantadine (Symmetrel) is better tolerated with older patients
Both of those can be used for extended prophylaxis, although not
Levodopa may be helpful, but not always

Tardive Dyskinesia - Epidemiology

Higher chance with longer durations of treatment
20-30% chance for patients on typical antipsychotics
Elderly have the highest incidence and prevalence of tardive dyskinesia

5 times more as likely to develop than younger patients

Risk with atypicals up to 1/5 compared to that of typicals

Can occur with antiepileptics, lithium, oral contraceptives, and SSRIs

Tardive Dyskinesia - Pathophysiology

Various hypotheses regarding neurochemicals
Striatal dopaminergic hypersensitivity - most popular
Cholinergic deficiency within the basal ganglia
Dysfunctions of striatonigral GABA mediated neurons
Glutamate induced excitotoxicity - caused by chronic dopamine blockade
Oxidative stress - caused by increased dopamine turnover

Tardive Dyskinesia - Clinical Features

Characterized by involuntary choreiform, athetoid, and stereotypic movements
Commonly affects mouth, face, and limbs
Blinking, chewing, lower jaw movements, grimacing, lip puckering and smacking, tongue
protrusion, facial tic-like movements
Remission is rare if the offending drug is continued

Can occur with withdrawal of drug

Can be unmasked if the typical antipsychotic is switched to an atypical

Tardive Dyskinesia - Clinical Features

Abnormal Involuntary Movement Scale (AIMS):

Rates dyskinetic movements in 7 body regions

Also tests global severity, functional impairment, and self-awareness of

Symptoms can worsen with antimuscarinics, sympathomimetic stimulants, or

emotional extremes
Can be repressed with voluntary movement of affected body

Tardive Dyskinesia - Risk Factors

Advanced Age - more severe and irreversible

History of extrapyramidal reaction
Intermittent neuroleptic treatment
Duration of treatment
Iron Deficiency
Mental retardation
Organic brain disorder

Tardive Dyskinesia - Morbidity and Mortality

Remission is low if drug is continued
Symptoms may resolve if drug is removed but may take months to years
Patients may have difficulty chewing, swallowing, or speaking
Gait abnormalities may cause falls

Tardive Dyskinesia - Therapeutic Management

Start with low dose of antipsychotics to decrease unnecessary drug exposure
Intermittent removal of drug has an increased risk of tardive dyskinesia and
psychosis relapse
Early detection is important
Switch to atypical antipsychotic, discontinue anticholinergic, start adjunctive
vitamin E or benzodiazepine
Older people less likely to have remission