Extrapyramidal Symptoms (EPS)

Pathophysiology

Types of EPS

1. Akathisia

• Most common acute EPS
• Greek: akathizein = "inability to sit still"
• Symptoms: inner restlessness, compulsion to move, shifting weight, rocking, pacing, leg restlessness; can manifest as anxiety, irritability, or even aggression
• Onset: usually within days 2–5 of antipsychotic initiation; can be hours after IM dosing
• ~41% develop mild akathisia, ~21% moderate-to-severe with dopamine antagonists
• Severe akathisia has been linked to suicidal ideation and aggressive behavior — a dangerous clinical trap where clinicians may incorrectly increase the antipsychotic dose, worsening the symptom
• Rating scale: Barnes Akathisia Rating Scale (BARS); Simpson–Angus EPS Scale

2. Acute Dystonia

• Most frightening EPS; onset within hours to 3 days (10% within first hours; 90% within first 3 days)
• Intermittent or sustained involuntary muscle spasms affecting head, neck, trunk, extremities
• Common forms:
  • Torticollis / retrocollis — neck twisting
  • Oculogyric crisis — eyes forced upward
  • Opisthotonos — rigid arching of the back
  • Macroglossia / tongue protrusion — can cause choking
  • Laryngeal dystonia — rare but potentially fatal (airway emergency)
  • Trismus / jaw spasm
• Risk factors: young males, high-potency FGAs, large doses
• Responds rapidly to anticholinergics or antihistamines (IM/IV)

3. Drug-Induced Parkinsonism (DIP)

• Affects ~30% of FGA-treated patients
• Onset: 5–30 days of treatment
• Symptoms mirror idiopathic Parkinson's disease:
  • Tremor (resting), muscular rigidity, bradykinesia, shuffling gait
  • Masked facies, decreased arm swing, hypersalivation
  • Bradyphrenia (slowed thinking)
  • Positive glabella tap
• Can be mistaken for depression or negative symptoms of schizophrenia (important clinical pitfall)
• Risk factors: older age, high dose, FGA use, prior parkinsonism, basal ganglia damage (e.g., vascular)

4. Tardive Dyskinesia (TD)

• Develops after months to years of dopamine blocker use; may persist after discontinuation
• Prevalence: ~4–5% per year of treatment; up to 15–20% in chronically treated patients
• Movements:
  • Oro-facial: lip smacking, sucking, puckering, tongue protrusion (fly-catching), facial grimacing
  • Limbs: choreoathetoid finger/toe movements
  • Trunk: slow writhing movements
• Differential: Huntington disease, Wilson disease, Sydenham chorea, hyperthyroidism, L-dopa dyskinesia
• Mechanism: dopamine receptor upregulation/supersensitivity in basal ganglia
• Higher risk: older women, affective disorders, high cumulative dose, prior acute EPS
• Antiparkinsonian drugs (anticholinergics) worsen TD
• Paradoxically suppressed (masked) by increasing the antipsychotic dose — but this is not appropriate management

5. Perioral Tremor ("Rabbit Syndrome")

• Uncommon; appears after months to years
• Vertical tremor of the lips/mouth resembling a rabbit's chewing motion
• Distinct from TD; responds to anticholinergics

Comparative Summary Table

Risk Stratification by Drug

• Highest EPS risk: Haloperidol, fluphenazine, perphenazine (high-potency FGAs)
• Lower EPS risk (SGAs): Olanzapine, quetiapine, aripiprazole, lurasidone
• Lowest EPS risk: Clozapine, quetiapine (dose-dependent exceptions)

Management

Acute Dystonia

• IM/IV diphenhydramine 50 mg (25 mg in children) — response within minutes IV, ~20 min IM
• IM/IV benztropine 0.5–2 mg
• Laryngospasm = medical emergency → immediate IV anticholinergic

Drug-Induced Parkinsonism

• Reduce antipsychotic dose
• Add anticholinergic (benztropine 1–6 mg/day; trihexyphenidyl 1–15 mg/day)
• Switch to lower-EPS SGA (e.g., clozapine)
• Amantadine (100 mg twice daily) — second-line; dopamine-releasing agent
• Avoid direct dopamine agonists (levodopa, bromocriptine) — may worsen psychosis

Akathisia

• First-line: β-blocker (propranolol 30–80 mg/day) — preferred by many clinicians
• Reduce antipsychotic dose or switch to lower-EPS agent
• Benzodiazepines (clonazepam)
• 5-HT₂A antagonists: mirtazapine, cyproheptadine, trazodone
• Anticholinergics: less effective unless part of broader EPS spectrum

Tardive Dyskinesia

• Stop anticholinergics (they worsen TD)
• Reduce/taper antipsychotic dose gradually
• Switch to clozapine (most likely to resolve TD)
• Valbenazine (40–80 mg/day) — FDA-approved; VMAT2 inhibitor
• Deutetrabenazine (6 mg twice daily up to 48 mg/day) — FDA-approved; VMAT2 inhibitor
• Tetrabenazine, Ginkgo biloba — some evidence
• ECT may benefit severe dystonic TD

Prophylaxis

• Prophylactic anticholinergics considered for high-risk patients (young males starting high-potency FGAs)
• WHO consensus: anticholinergics are overprescribed as prophylaxis; reserve for high-risk patients; review every 3 months

Monitoring

• Patients on dopamine blockers >6 months should have regular TD screening using the Abnormal Involuntary Movement Scale (AIMS)
• Simpson–Angus EPS Scale and Barnes Akathisia Rating Scale for acute EPS monitoring

Recent evidence note (2024): A network meta-analysis (PMID 38682452) confirmed propranolol as among the most effective treatments for antipsychotic-induced akathisia, consistent with established guidelines. No major changes to core EPS management paradigms have emerged in 2024–2026.