Extrapyramidal Side Effects (EPS)
Summary
Extrapyramidal side effects (EPS) represent a spectrum of drug-induced movement disorders caused primarily by the blockade of dopamine D2 receptors in the nigrostriatal pathway. They are a major limiting factor in the use of antipsychotic medications (neuroleptics) and antiemetics (e.g., metoclopramide). EPS follows a predictable chronological timeline: Acute Dystonia (hours to days), Akathisia (days to weeks), Drug-Induced Parkinsonism (weeks to months), and Tardive Dyskinesia (months to years).
Recognising EPS is critical because they cause significant patient distress, lead to medication non-adherence, and carry risks of permanent disability (tardive dyskinesia) or life-threatening complications (laryngospasm, Neuroleptic Malignant Syndrome). While second-generation (atypical) antipsychotics have a lower risk profile compared to first-generation (typical) agents, EPS remain a common clinical challenge.
Historical Context
The term "extrapyramidal" distinguishes these motor symptoms from those arising from the pyramidal tract (corticospinal tract). Historically, the development of chlorpromazine in the 1950s revolutionised psychiatry but introduced these "neuroleptic" (nerve-seizing) effects. For decades, it was believed that therapeutic efficacy required EPS (the "neuroleptic threshold"), but the advent of clozapine proved that antipsychotic action could be dissociated from motor side effects. Today, the goal is "neurolepsis without EPS".
Key Facts
- Primary Mechanism: Dopamine D2 receptor antagonism in the basal ganglia (nigrostriatal tract).
- Causative Agents: Typical antipsychotics (haloperidol, chlorpromazine), atypical antipsychotics (risperidone, olanzapine - dose dependent), antiemetics (metoclopramide, prochlorperazine).
- Four Cardinal Types:
- Acute Dystonia: Sustained muscle contractions (e.g., torticollis, oculogyric crisis).
- Akathisia: Subjective inner restlessness and objective motor fidgeting.
- Parkinsonism: Tremor, rigidity, bradykinesia ("pseudoparkinsonism").
- Tardive Dyskinesia: Involuntary choreoathetoid movements after chronic exposure.
- Treatment Hierarchy:
- Dystonia/Parkinsonism: Anticholinergics (procyclidine, benztropine).
- Akathisia: Beta-blockers (propranolol), benzodiazepines.
- Tardive Dyskinesia: VMAT2 inhibitors (valbenazine), switch to clozapine.
Clinical Pearls
"The EPS Timeline": Remember the rule of 4s (approximation):
- 4 hours: Acute Dystonia
- 4 days: Akathisia
- 4 weeks: Parkinsonism
- 4 months (to years): Tardive Dyskinesia
"Dystonia implies youth, TD implies age": Acute dystonia is predominantly a disease of young, drug-naive males. Tardive dyskinesia is predominantly a disease of elderly females with chronic exposure.
"Procyclidine is Diagnostic and Therapeutic": If you suspect acute dystonia but aren't sure, a test dose of parenteral procyclidine or benztropine usually provides relief within minutes, confirming the diagnosis.
"Akathisia is a Suicide Risk": The intense internal restlessness of akathisia ("jumping out of one's skin") is heavily correlated with treatment discontinuation and suicide attempts. Never dismiss a patient who says they "cannot sit still" after starting an antipsychotic.
"Clozapine is the Safe Haven": Clozapine has the lowest affinity for D2 receptors and is the only antipsychotic proven to not cause tardive dyskinesia (and may improve existing TD). Quetiapine is the next best option.
"Anticholinergics Worsen Tardive Dyskinesia": While they treat parkinsonism and dystonia, anticholinergics can unmask or exacerbate tardive dyskinesia (TD). If TD appears, stop the anticholingeric first.
Incidence and Prevalence
The incidence of EPS varies significantly based on the class of medication used, the dose, and individual patient susceptibility.
| EPS Subtype | Typical Antipsychotics | Atypical Antipsychotics | High-Risk Demographics |
|---|---|---|---|
| Acute Dystonia | 2% - 10% (up to 50% in high-risk) | < 2% | Young males, cocaine use, naive patients |
| Akathisia | 20% - 40% | 5% - 15% | Middle-aged females, high potency agents |
| Parkinsonism | 20% - 40% | 5% - 10% | Elderly, females, pre-existing neurological damage |
| Tardive Dyskinesia | 5% per year (cumulative) | 0.5% - 1% per year | Elderly, females, mood disorders, diabetes |
Pharmacolgenomics
Genetic variability plays a significant role in individual susceptibility to EPS.
- CYP2D6 Metabolism: This enzyme metabolises many antipsychotics (haloperidol, risperidone, aripiprazole).
- Poor Metabolisers (PM): Have higher plasma drug concentrations at standard doses, leading to increased EPS risk.
- Ultra-Rapid Metabolisers (UM): Have lower levels, leading to lack of efficacy.
- DRD2 Polymorphisms: Variations in the dopamine D2 receptor gene (Taq1A allele) are associated with increased risk of Tardive Dyskinesia.
- HTR2A Polymorphisms: Serotonin 2A receptor variations may affect the "atypicality" of drugs and therefore EPS liability.
Potency and Risk Correlation (Receptor Occupancy)
The risk of EPS is directly proportional to D2 receptor occupancy in the striatum.
D2 RECEPTOR OCCUPANCY & CLINICAL EFFECTS
0% -------------------------------------------------- 100%
[ Sub-therapeutic Range (less than 60%) ]
[ Therapeutic Window (60-80%) ]
[ EPS Threshold (>80%) ]
- >80% Occupancy: High risk of EPS.
- 60-80% Occupancy: Therapeutic window for antipsychotic effect.
- less than 60% Occupancy: Lack of efficacy.
- Exceptions: Clozapine and Quetiapine loosen quickly from D2 receptors ("Fast-off theory"), reducing EPS risk even at high doses.
Risk Factors
Medication-Related:
- Potency: High-potency D2 blockers (e.g., haloperidol, fluphenazine) > Low-potency (e.g., chlorpromazine).
- Dose: Linear relationship; higher cumulative doses increase TD risk.
- Route: Parenteral (IM/IV) administration increases risk of acute dystonia.
- Rapid Escalation: Fast outcomes in titration increase akathisia risk.
- Polypharmacy: Concomitant use of lithium or SSRIs can increase EPS risk via pharmacokinetic interactions (CYP inhibition).
Patient-Related:
- Age: Younger patients (> dystonia), Older patients (> parkinsonism, TD).
- Gender: Males (> dystonia), Females (> akathisia, TD).
- Genetics: CYP2D6 poor metabolizers have higher drug levels. polymorphisms in DRD2 and DRD3 genes are being investigated to predict susceptibility.
- Co-morbidities: HIV/AIDS, organic brain damage, Lewy Body Dementia, Iron deficiency (associated with akathisia).
The Dopamine-Acetylcholine Balance
The basal ganglia control motor tone and coordination via a delicate balance between dopamine (inhibitory influence on Cholinergic neurons) and acetylcholine (excitatory influence).
Figure 1: Pathophysiology of EPS showing Nigrostriatal D2 Blockade
Mechanism by Subtype
Step 1: Nigrostriatal Blockade (The "Parkinsonian" Mechanism)
- Antipsychotics block postsynaptic D2 receptors in the striatum.
- Normal State: Dopamine released from the substantia nigra inhibits intrinsic cholinergic interneurons in the striatum.
- Blockade State: Loss of dopamine inhibition leads to disinhibition and relative cholinergic excess.
- Result: Muscle rigidity, tremor, and acute muscle spasms (Dystonia/Parkinsonism).
- Treatment Rationale:
- Anticholinergics: Block the excess acetylcholine to restore the balance.
- Dopamine Agonists: (e.g. Bromocriptine) Directly stimulate D2 receptors, but can worsen psychosis, so are avoided.
Step 2: Receptor Upregulation (The "Tardive" Mechanism)
- Chronic blockade of D2 receptors leads to compensatory hypersensitivity and upregulation (increase in number) of postsynaptic receptors.
- The system becomes supersensitive to any available dopamine.
- Result: Even normal physiological dopamine levels cause excessive signaling, leading to hyperkinetic movements (Tardive Dyskinesia) - the clinical opposite of parkinsonism.
- Note: This explains why increasing the antipsychotic dose temporarily masks TD (by blocking the new receptors), but ultimately worsens the underlying pathology.
- Oxidative Stress: There is also a theory that neurotoxic free radicals produced by metabolism of antipsychotics contribute to neuronal damage in TD.
Step 3: Other Pathways (Akathisia)
- The mechanism of akathisia is poorly understood but is distinct from the other EPS.
- Likely involves a mismatch between norepinephrine (adrenergic) and dopamine systems in the shell of the nucleus accumbens and prefrontal cortex.
- This explains why beta-blockers (propranolol) are effective, whereas anticholinergics are generally ineffective for akathisia.
Receptor Binding Profile of Common Antipsychotics
| Drug | D2 Affinity (EPS Risk) | 5HT2A Affinity (Atypicality) | H1 Affinity (Weight/Sedation) | M1 Affinity (Anticholinergic) | Clinical Correlate |
|---|---|---|---|---|---|
| Haloperidol | High | Low | Low | Low | High EPS risk, low sedation. |
| Olanzapine | Moderate | High | High | High | Metabolic syndrome, sedation. Intrinsic anticholinergic effect reduces EPS but worsens cognition. |
| Quetiapine | Low (Transient) | Moderate | High | Moderate | Very low EPS (loosens from receptor quickly). High sedation. |
| Clozapine | Low | High | High | High | No EPS. First line for TD. Risk of agranulocytosis. |
| Aripiprazole | Partial Agonist | High | Moderate | Low | Low EPS but high Akathisia risk (partial agonism creates 'noise'). |
1. Acute Dystonia (Emergency)
Onset: Hours to 5 days (90% within 3 days).
2. Akathisia (The "Restless" Syndrome)
Onset: Days to weeks.
3. Drug-Induced Parkinsonism
Onset: Weeks to months.
4. Tardive Dyskinesia (TD)
Onset: Months to years (usually > 3-6 months).
Red Flags
[!WARNING] Laryngospasm: Acute dystonia affecting the larynx can cause fatal upper airway obstruction. Treat immediately with IV/IM anticholinergics.
[!CAUTION] Neuroleptic Malignant Syndrome (NMS): Differentiate severe parkinsonism from NMS. NMS presents with fever, autonomic instability (labile BP/HR), and elevated creatine kinase (CK). Rigidity in EPS is just rigidity; Rigidity + Fever = NMS.
Distinguishing EPS from other movement disorders and psychiatric states is vital.
| Condition | Distinguishing Features |
|---|---|
| Psychotic Agitation | Driven by fear/delusions; no leg-specific restlessness; improves with antipsychotics (akathisia worsens). |
| Neuroleptic Malignant Syndrome | FEVER (>38°C), Confusion, Autonomic Instability, Elevated CK (>1000). Rigidity is "lead pipe". |
| Serotonin Syndrome | Hyperreflexia, Clonus (inducible/spontaneous), Dilated pupils (mydriasis). Usually history of SSRI/MAOI use. |
| Catatonia | Waxy flexibility, mutism, negativism, stupor. Treat with benzodiazepines. |
| Huntington's Disease | Family history, cognitive decline precedes movement, caudate atrophy on MRI. |
| Wilson's Disease | Hepatic involvement, Kayser-Fleischer rings, low caeruloplasmin. Young onset. |
| Lewy Body Dementia | Visual hallucinations, fluctuating cognition, sensitivity to antipsychotics (severe EPS with low doses). |
| Functional Movement Disorder | Distractibility, variability, entrainment (movements change rhythm to match external tapped rhythm). |
| Restless Legs Syndrome | Worse at night/rest, relieved by movement (akathisia is constant but worse at rest). |
| Meige Syndrome | Oral-facial dystonia + blepharospasm. Often idiopathic. |
Structured Approach
1. Observation (General)
- Observe patient at rest and while talking.
- Look for restlessness (akathisia) or abnormal posture (dystonia).
- Observe gait: Check for arm swing and turning speed.
2. Face and Mouth (TD Assessment)
- Ask patient to open mouth and stick out tongue.
- Look for tongue tremor, worm-like movements, or inability to keep tongue extruded.
- Observe for lip smacking or chewing.
- "Bon-bon sign": Tongue pushing against cheek.
3. Upper Limbs
- Tone: Assess for 'cogwheel' rigidity (tremor superimposed on tone) at the wrist and elbow. Reinforce tone by asking patient to tap opposite hand (Froment's maneuvre).
- Tremor: Assess resting tremor (pill-rolling).
- Bradykinesia: Finger tapping test (slow, decremental amplitude).
- Pronator Drift: To exclude pyramidal weakness.
4. Lower Limbs and Gait
- Tone: Lead-pipe rigidity.
- Gait: Observe arm swing (loss of swing is an early sign), turning (en bloc turning), and stride length.
- Tap Test: Ask patient to tap foot rapidly. In parkinsonism, amplitude decreases.
- Retropulsion: Pull test (be careful!) to check postural stability.
Scales and Tools
- AIMS (Abnormal Involuntary Movement Scale): Gold standard for monitoring TD. Should be performed every 6-12 months.
- Score 0-4 for 7 body areas.
- Positive if ≥2 in one area or ≥1 in two areas.
- BARS (Barnes Akathisia Rating Scale): Assesses subjective and objective akathisia.
- SAS (Simpson-Angus Scale): Specifically for parkinsonism.
- DISCUS: Dyskinesia Identification System: Condensed User Scale.
EPS is primarily a clinical diagnosis, but investigations exclude other causes.
| Modality | Test | Rationale |
|---|---|---|
| Bloods | U&Es, Calcium, Magnesium | Hypocalcaemia predisposes to dystonia (tetany). |
| Creatine Kinase (CK) | Rule out Neuroleptic Malignant Syndrome (NMS) if rigidity is severe. | |
| Caeruloplasmin | Rule out Wilson's Disease in young patients with movement disorders (mandatory if less than 50yrs). | |
| Thyroid Function | Hyperthyroidism can mimic tremor/akathisia. | |
| Anti-NMDA Receptor Abs | If psychiatric presentation is atypical with movement disorder. | |
| Ferritin / Iron studies | Low iron supports diagnosis of akathisia or RLS. | |
| Imaging | CT/MRI Brain | Exclude basal ganglia pathology (stroke, tumour, calcification/Fahr's disease) if presentation is unilateral or atypical. |
| DaT Scan | Differentiate drug-induced parkinsonism (normal scan) from idiopathic PD (abnormal scan) - rare usage. | |
| Review | Drug Levels | Check lithium or digoxin levels if relevant (toxicity can mimic EPS). |
Management Algorithm
Figure 2: Stepwise Management of EPS Subtypes
SUSPECTED EXTRAPYRAMIDAL SIDE EFFECT
↓
┌────────────────────────────────────────────────────────────┐
│ STEP 1: IDENTIFY THE TYPE │
│ - Acute Dystonia (Spasm) │
│ - Akathisia (Restlessness) │
│ - Parkinsonism (Rigidity/Tremor) │
│ - Tardive Dyskinesia (Abnormal Movements) │
└────────────────────────────────────────────────────────────┘
↓
┌───────────┴───────────┐
ACUTE / EARLY LATE / CHRONIC
(Dystonia, Akathisia, Park.) (Tardive Dyskinesia)
↓ ↓
┌─────────────────────────────┐ ┌─────────────────────────────┐
│ General Measures: │ │ General Measures: │
│ 1. Stop Causative Agent? │ │ 1. Stop Anticholinergics │
│ 2. Reduce Dose? │ │ 2. Reduce Antipsychotic │
│ 3. Switch to Atypical │ │ 3. Switch to Clozapine │
│ (Quetiapine/Clozapine) │ │ │
└─────────────┬───────────────┘ └─────────────┬───────────────┘
│ │
┌─────────────┴───────────────┐ ┌─────────────┴───────────────┐
│ SPECIFIC TREATMENT │ │ SPECIFIC TREATMENT │
│ │ │ │
│ Dystonia: │ │ First Line: │
│ ➤ Procyclidine 5-10mg IM/IV │ │ ➤ VMAT2 Inhibitors │
│ ➤ Benztropine 1-2mg IM │ │ (Valbenazine/Deutetrabe- │
│ │ │ nazine) │
│ Akathisia: │ │ │
│ ➤ Propranolol 30-80mg │ │ Second Line: │
│ ➤ Clonazepam 0.5mg │ │ ➤ Tetrabenazine │
│ │ │ ➤ Clonazepam │
│ Parkinsonism: │ │ ➤ Ginko Biloba (adjunct) │
│ ➤ Oral Anticholinergics │ │ │
│ ➤ Amantadine │ │ │
└─────────────────────────────┘ └─────────────────────────────┘
Detailed Pharmacotherapy
1. Anticholinergics (Muscarinic Antagonists)
The cornerstone of treatment for Dystonia and Parkinsonism.
- Agents: Procyclidine, Benztropine (Cogentin), Trihexyphenidyl (Artane), Biperiden.
- Mechanism: Restores Dopamine:Acetylcholine balance by inhibiting cholinergic excess in the striatum.
- Dose (Procyclidine):
- Acute: 5–10 mg IM or IV (slow push). Relief usually within 5-20 mins (IM) or 2-5 mins (IV).
- Maintenance: 2.5–5 mg TDS oral. Max 30mg/day.
- Duration: Usually 3-6 months, then attempt to withdraw.
- Dose (Benztropine):
- 1-2 mg IM/IV stat, then 1-2 mg BD oral. Longer half-life than procyclidine.
- Side Effects: Dry mouth (xerostomia), blurred vision (cycloplegia), urinary retention, constipation, tachycardia, cognitive decline (avoid in elderly due to delirium risk).
- Warning: Can be abused using "buzz" potential.
2. Beta-Blockers
First-line for Akathisia.
- Agent: Propranolol (lipophilic, crosses blood-brain barrier).
- Dose: 10 mg BD initially, titrate to 40–80 mg daily.
- Mechanism: Central beta-blockade. Peripheral beta-blockers (atenolol) are less effective.
- Note: Monitor BP and HR. Contraindicated in asthma/COPD.
3. Benzodiazepines
Second-line for Akathisia and Dystonia (if anticholinergics fail/contraindicated).
- Agents: Clonazepam, Diazepam, Lorazepam.
- Role: Symptomatic relief of anxiety and muscle relaxation.
- Risk: Sedation, dependence.
4. VMAT2 Inhibitors
Standard of care for Tardive Dyskinesia.
- Agents: Valbenazine, Deutetrabenazine, Tetrabenazine.
- Mechanism: Inhibits Vesicular Monoamine Transporter 2 (VMAT2), depleting presynaptic dopamine stores, thus reducing hyperkinetic movements.
- Evidence: ARM-TD and KINECT trials demonstrate significant reduction in AIMS scores.[1,2]
- Comparison:
- Tetrabenazine: Short half-life (TDS dosing), high peak concentrations, higher risk of depression/suicidality and parkinsonism.
- Deutetrabenazine: Deuterated form, longer half-life (BD dosing), smoother profile, better tolerability.
- Valbenazine: Prodrug, OD dosing, best tolerability profile.
- Pros: Do not worsen psychiatric symptoms (unlike dopamine blockade).
- Cons: Cost (expensive), risk of depression (tetrabenazine > others).
5. Switching Strategies (Cross-Tapering Protocols)
If EPS persists, switching is often necessary. D2 affinity determines risk. Target Drugs: Quetiapine, Aripiprazole, or Clozapine.
| Week | Current Antipsychotic (e.g. Haloperidol) | New Antipsychotic (e.g. Quetiapine) |
|---|---|---|
| 1 | 75% Dose | 25% Target Dose |
| 2 | 50% Dose | 50% Target Dose |
| 3 | 25% Dose | 75% Target Dose |
| 4 | Stop | 100% Target Dose |
Note: Aripiprazole has high D2 affinity (as partial agonist) and should be introduced slowly to avoid displacing the current drug too rapidly, which can cause rebound psychosis.
1. The Elderly (>65 Years)
- High Risk: Very susceptible to Parkinsonism and Tardive Dyskinesia. Age is the strongest predictor for TD.
- Management:
- Avoid anticholinergics (risk of cognitive decline, falls, urinary retention). Acetylcholinesterase inhibitors (Donepezil) are used for dementia - anticholinergics oppose this.
- "Start low, go slow".
- Prefer atypical agents (quetiapine) or low-dose risperidone.
- Monitor for aspiration (dysphagia).
2. Pregnancy
- Risk: EPS can occur in the foetus (withdrawal dyskinesia) if mother is on high doses in 3rd trimester.
- Management: Lowest effective dose. Avoid prophylactic anticholinergics (risk of foetal ileus).
- Breastfeeding: Monitor infant for sedation or muscle stiffness.
3. Children and Adolescents
- High Risk: Particularly prone to Acute Dystonia.
- Management:
- Avoid high-potency typicals.
- Aripiprazole is often preferred but monitor for akathisia.
- Lurasidone is FDA approved for adolescents.
4. Intellectual Disability
- Higher baseline risk of TD.
- Consent issues regarding monitoring and medication changes.
- Ensure AIMS checks are regular (every 3-6 months).
- Behavioural changes may mask akathisia (e.g., self-injury).
Case 1: The Stiff Neck (Acute Dystonia)
Scenario: James, a 24-year-old male with first-episode psychosis, was admitted yesterday and started on Haloperidol 5mg. He is found by nursing staff in distress, his head twisted to the left and unable to move it back. He is frightened and struggling to swallow. Diagnosis: Acute Dystonia (Torticollis). Management:
- Stop Haloperidol immediately.
- Administer Procyclidine 5-10 mg IM.
- Reassure James (this is a drug reaction, not the illness).
- Monitoring for airway patency.
- Once resolved, switch to an atypical antipsychotic (e.g., Olanzapine).
Case 2: The "Anxious" Pacer (Akathisia)
Scenario: Sarah, a 45-year-old female with depression with psychotic features, had her Aripiprazole increased to 15mg last week. She reports feeling "crawling skin" and that her anxiety is "unbearable". Staff note she is pacing the corridor constantly. Diagnosis: Akathisia. Management:
- Do not interpret as worsening anxiety.
- Reduce Aripiprazole dose back to tolerated level.
- Start Propranolol 10mg BD.
- If agitation persists, consider switching to Quetiapine.
Case 3: The Chewing Motion (Tardive Dyskinesia)
Scenario: Robert, 68, has been on Depot Zuclophenthixol for 20 years for Schizophrenia. During a review, you notice he is constantly chewing, though he is not eating, and his tongue darts out occasionally. Diagnosis: Tardive Dyskinesia. Management:
- Perform AIMS assessment (Score confirm TD).
- Review medication: Can the depot be reduced?
- Stop any anticholinergics (e.g., Procyclidine) immediately.
- Consideration switching to Clozapine (the only drug to reduce TD).
- If switch not possible, start Valbenazine.
Physical Complications
- Fractures/Falls: Due to rigidity, bradykinesia, and gait instability.
- Rhabdomyolysis: Secondary to severe dystonia or untreated NMS. CK levels rise, risk of acute kidney injury.
- Dysphagia: Pharyngeal muscle dysfunction leading to silent aspiration and pneumonia (common cause of death in elderly on antipsychotics).
- Dental pathology: Broken teeth, gum hypertrophy, or tongue trauma from severe dystonia or TD.
- Weight Loss: In severe akathisia due to constant movement.
Psychosocial Complications
- Treatment Resistance: Patients refuse medication due to side effects ("Non-adherence"). This leads to relapse and rehospitalisation.
- Stigma: Visible movement disorders (TD) can be socially isolating and label the patient as "mentally ill".
- Suicide: Specifically linked to untreated akathisia due to the intense dysphoria.
- Quality of Life: Significant reduction in ADLs due to tremor or rigidity.
The prognosis depends heavily on the type of EPS and speed of intervention.
| EPS Type | Reversibility | Prognostic Factors |
|---|---|---|
| Dystonia | 100% reversible | Responds immediately to treatment. No long-term sequelae if airway managed. Recurrence is common if anticholinergics not continued for 48hrs. |
| Akathisia | Reversible | Often persists if drug continued. Disappears on cessation. Can become chronic (tardive akathisia) in rare cases. |
| Parkinsonism | Reversible | May take weeks to resolve after drug cessation due to slow washout (esp. depots). Some elderly patients may have unmasked idiopathic PD. |
| Tardive Dyskinesia | Potentially Permanent | 30-50% cases are irreversible even after stopping the drug. Remission rates are higher if caught early (< 3 months). VMAT2 inhibitors provide symptomatic relief but may not "cure" the underlying pathology. Spontaneous remission is rare in elderly. |
Landmark Trials
- CUtLASS 1 (2006): Compared First vs Second Generation antipsychotics. Found no significant difference in quality of life but confirmed higher EPS rates in the typical group if not managed carefully.[3]
- CATIE (2005): Large effectiveness trial. Showed high discontinuation rates across all drugs. Perphenazine (classic) had similar efficacy to atypicals but more EPS issues. It highlighted that newer drugs are not panaceas.[4]
- KINECT-3 (2015): Pivotal Phase 3 trial for Valbenazine. Demonstrated significant improvement in Tardive Dyskinesia severity (AIMS score reduction) without worsening psychiatric status.[1]
- ARM-TD (2017): Demonstrated efficacy of Deutetrabenazine for TD with a favourable safety profile compared to tetrabenazine.[2]
Guideline Recommendations
- NICE (CG178 - Psychosis, 2014):
- Offer oral anticholinergics for acute dystonia.
- Do NOT prescribe anticholinergics routinely for prevention (only if symptoms emerge).
- Monitor for TD annually (AIMS).
- Maudsley Prescribing Guidelines (15th Ed):
- Propranolol is first-line for akathisia.
- Clozapine is the drug of choice for psychosis with TD.
- Switch to an atypical with lower D2 occupancy/affinity (Quetiapine, Aripiprazole).
- APA Guidelines: Recommend VMAT2 inhibitors as first-line treatment for moderate-to-severe TD.
What is happening to my body?
These are physical side effects caused by your medication interfering with the chemical messengers (dopamine) that control movement. It is not "in your head" - it is a real physical reaction. Just like insulin lowers blood sugar, these drugs lower "movement chemical" levels.
The different types explained:
- Acute Dystonia: "Muscle Cramp". Your muscles lock up, often in the neck or jaw. It is scary but can be fixed instantly with an injection.
- Akathisia: "Restlessness". You feel like you have drunk 10 coffees and cannot sit down. This is very uncomfortable, but we have medicines to calm it.
- Parkinsonism: "Stiffness". You might feel slow, stiff, or have a shake in your hands, similar to Parkinson's disease. This goes away if we change the dose.
- Tardive Dyskinesia: "Twitching". Use of these medicines for a long time can cause automatic movements of the mouth or face. We check for this regularly to stop it before it settles in.
What should I do?
Never just stop your medication suddenly, as you might get unwell again. Tell your doctor immediately if:
- Your neck or jaw feels stiff (e.g., cannot turn head).
- You feel so restless you can't watch TV or sit for a meal.
- You notice any twitching in your face or tongue.
- You have trouble swallowing.
Information Leaflet: Taking Procyclidine
- Why?: To relax stiff muscles caused by antipsychotics.
- How long?: Usually for a few months until your body adjusts.
- Side effects: Dry mouth (suck sugar-free sweets), slight blurriness of vision (caution driving), constipation (drink plenty of water).
- Stopping: Do not stop suddenly; your muscle stiffness might come back.
Frequently Asked Questions
Q: Will I have this forever? A: Most types (stiffness, restlessness) go away when we adjust the dose. Tardive dyskinesia (twitching) can be permanent, which is why we monitor you closely.
Q: Can I drive? A: If you have stiff muscles or blurred vision from the antidote, you should not drive. If you are stable, it is usually fine.
Q: Can I drink alcohol? A: Alcohol can make the sedation and unsteadiness worse. It is best to avoid it while stabilizer your dose.
- Recognition is Key: Acute dystonia is a medical emergency; akathisia is a psychiatric emergency (suicide risk).
- Procyclidine: Is the antidote for Dystonia and Parkinsonism, but NOT for Akathisia or Tardive Dyskinesia.
- Propranolol: Is the treatment for Akathisia.
- Prevention: "Start low, go slow" and prefer atypicals with low D2 affinity (Quetiapine, Aripiprazole).
- Monitoring: Perform AIMS annually (or more frequently in high-risk groups) to detect Tardive Dyskinesia early.
- Tardive Dyskinesia: Is potentially irreversible; stop anticholinergics first, then consider switching to Clozapine or adding a VMAT2 inhibitor.
- Hauser RA, et al. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry. 2017;174(5):476-484. [PMID: 28320223].
- Fernandez HH, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Deutetrabenazine for Tardive Dyskinesia: The ARM-TD Study. Neurology. 2017;88(21):2003-2010. [PMID: 28446654].
- Jones PB, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006;63(10):1079-1087. [PMID: 17015810].
- Lieberman JA, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia (CATIE). N Engl J Med. 2005;353(12):1209-1223. [PMID: 16172203].
- Rummel-Kluge C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123(2-3):225-233. [PMID: 20932736].
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Common Exam Questions (MRCP/MRCPsych)
Viva Question: "Differentiate between Akathisia and Agitation in a psychotic patient."
Answer: This is a crucial distinction because the treatments are opposite.
- Akathisia: Subjective inner restlessness ("I can't sit still"), predominantly affects legs (pacing, tapping), occurs after starting/increasing dose, worsens with antipsychotics. Treat with Propranolol.
- Agitation: Driven by psychotic delusions or fear, affects whole body/behaviour, not localized to legs, improves with antipsychotics. Treat with Benzodiazpines/Antipsychotics.
MCQ Pearl: "A patient develops a fixed upward gaze after receiving haloperidol. What is the immediate treatment?"
Answer: Procyclidine IM/IV. This is an Oculogyric Crisis (Acute Dystonia).
Pitfalls to Avoid
- Missing Laryngospasm: Always ask about breathing/stridor in dystonia cases.
- Misdiagnosing Akathisia: Do not mistake it for worsening psychosis and increase the antipsychotic dose (this creates a vicious cycle).
- Using Levodopa: Never use Levodopa for drug-induced parkinsonism in psychosis (it acts on D2 receptors and will worsen the psychosis). Use anticholinergics instead.