Extrapyramidal Side Effects (EPSE)

Overview

• Extrapyramidal side effects are drug-induced movement disorders most often associated with typical (first-generation) antipsychotics, though they can also occur with some atypical antipsychotics (particularly at higher doses). These side effects arise from dopamine D2 receptor blockade in the nigrostriatal pathway. The mnemonic “4 hours, 4 days, 4 weeks, 4 months” helps recall typical onset timelines of various EPSE.

1. Acute Dystonia (4 Hours)

• Symptoms:

  • Sudden muscle spasms (often affecting face, neck, back)

  • Oculogyric crisis (eyes deviated upward)

  • Laryngospasm (rare but potentially severe)

• Onset: Typically within hours of initiating or escalating dose (about 90% within 5 days, 50% within 2 days)

• Management:

  • IM benztropine (1 mg) or IV/IM anticholinergics

  • Transition to oral benztropine or other anticholinergic for short-term prophylaxis

  • If recurrent, consider dose reduction or switching antipsychotic

2. Akinesia (4 Days)

• Symptoms:

  • Parkinsonism features: Bradykinesia, rigidity, tremor, postural instability

  • May also present with masked facies or a shuffling gait

• Onset: Within days to weeks of antipsychotic use (often around 4 days in acute presentations)

• Management:

  • Oral benztropine (1–2 mg up to TDS) or trihexyphenidyl

  • Amantadine may be used if anticholinergics are contraindicated

  • Consider lowering dose of antipsychotic or switching to a lower-risk agent (e.g. second-generation antipsychotic)

3. Akathisia (4 Weeks)

• Symptoms:

  • Subjective restlessness, inner tension, inability to stay still

  • Patient may pace around, fidget, or shift weight frequently

  • Can significantly impact compliance with antipsychotics

• Onset: Usually within weeks of starting or increasing dose

• Management:

  • Propranolol (10–40 mg BD) often first-line

  • Benzodiazepines (e.g. diazepam) if severe anxiety

  • Dose reduction or switching to a lower-risk antipsychotic may help

  • Short-term use of anticholinergics is less effective for akathisia

4. Tardive Dyskinesia (4 Months)

• Symptoms:

  • Involuntary, repetitive movements, often orofacial (lip smacking, tongue protrusion) or choreoathetoid limb movements

  • Can be socially stigmatizing and sometimes irreversible

• Onset: Usually after months to years of antipsychotic therapy (the mnemonic “4 months” is a memory aid, but real onset can be much longer)

• Management:

  • Switch to a lower-risk agent (e.g. clozapine, quetiapine)

  • Consider reducing or discontinuing the offending drug if feasible

  • VMAT2 inhibitors (e.g. valbenazine, tetrabenazine) have emerging evidence to reduce tardive dyskinesia

  • Early recognition is key; permanent changes can occur if not addressed promptly

Additional Notes

• Risk Factors: Older age, higher doses, longer duration of antipsychotic use, presence of organic brain syndromes (e.g. dementia).

• Preventive Strategies: Use the lowest effective dose of antipsychotic; prefer second-generation agents (some still carry EPSE risk, albeit lower).

• Monitoring: Regular assessment of extrapyramidal function using tools like the Simpson-Angus Scale or the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia.

• Clinical Pearls: If early onset EPSE occur, addressing them quickly (dose adjustment, medication switch, or short-term anticholinergics) can prevent non-adherence and more severe complications.