What is the mechanism behind extra pyramidal side effects (EPS)?

Mechanism of Extrapyramidal Side Effects (EPS)

The primary mechanism behind extrapyramidal side effects (EPS) is the blockade of dopamine D2 receptors in the nigrostriatal pathway. 1

Pathophysiology of EPS

Extrapyramidal side effects occur due to dopamine blockade or depletion in the basal ganglia, specifically in the nigrostriatal pathway. This pathway is critical for normal motor function, and interference with dopaminergic transmission here leads to various movement disorders 2.

The nigrostriatal pathway connects the substantia nigra to the striatum and is primarily involved in motor control. When antipsychotic medications block D2 receptors in this pathway, they disrupt the normal balance of dopaminergic activity, resulting in EPS 1.

Key Mechanisms:

• Primary Mechanism: D2 receptor blockade in the nigrostriatal pathway 1, 3
• Secondary Factors:
  • Rate of drug association with D2 receptors (faster association correlates with higher EPS risk) 4
  • Relative selectivity for different dopamine receptor subtypes 5
  • Balance between dopaminergic and cholinergic activity in the basal ganglia 1

Types of Extrapyramidal Side Effects

1. Acute Dystonia:

   • Sudden spastic contractions of muscle groups
   • Typically occurs within first few days of treatment
   • Often affects neck muscles, eyes (oculogyric crisis), or torso
   • Risk factors: young age, male gender, high-potency antipsychotics 1

2. Drug-induced Parkinsonism:

   • Symptoms include bradykinesia, tremors, and rigidity
   • Mimics idiopathic Parkinson's disease
   • Usually develops within first 3 months of treatment 6

3. Akathisia:

   • Severe restlessness and inability to sit still
   • Often misinterpreted as anxiety or psychotic agitation
   • Common reason for medication noncompliance 1

4. Tardive Dyskinesia:

   • Late-onset involuntary movements
   • Can be permanent even after medication discontinuation
   • Requires regular monitoring with standardized scales 3

Medication Factors Affecting EPS Risk

High vs. Low Risk Antipsychotics:

• High-potency conventional antipsychotics (e.g., haloperidol) have greater EPS risk due to stronger D2 receptor blockade in the nigrostriatal pathway 1

• Low-potency conventional antipsychotics (e.g., chlorpromazine, thioridazine) have more anticholinergic effects but fewer EPS 1

• Atypical antipsychotics generally have lower EPS risk due to:

  • Combined serotonin-dopamine receptor antagonism
  • Faster dissociation from D2 receptors
  • Selective action on limbic rather than striatal dopamine pathways 5

Recent Research Insights:

Recent research has revealed that the association rate (how quickly drugs bind to D2 receptors) may be more important than dissociation rate in determining EPS risk 4. This challenges the traditional "fast-off" theory that focused primarily on dissociation rates.

Management of EPS

1. Acute Dystonia:

   • Anticholinergic medications (benztropine 1-2 mg) or antihistamines
   • Consider prophylaxis in high-risk patients 3, 7

2. Drug-induced Parkinsonism:

   • Reduce antipsychotic dose if clinically feasible
   • Add anticholinergic agent (benztropine 1-2 mg/day)
   • Consider amantadine as alternative
   • Evaluate switching to atypical antipsychotic 3, 7

3. Akathisia:

   • Reduce antipsychotic dose if possible
   • Beta-blockers (propranolol) are most effective
   • Benzodiazepines may provide relief
   • Anticholinergics are less consistently effective 3, 6

Clinical Implications

Understanding the mechanism of EPS is crucial for:

1. Medication selection: Choose antipsychotics with lower EPS risk when possible
2. Dose optimization: Use lowest effective dose to minimize D2 blockade
3. Early recognition: Identify and address EPS before they become severe or persistent
4. Appropriate management: Select targeted interventions based on specific EPS type

Common Pitfalls and Caveats

• Misdiagnosis: Akathisia is frequently misinterpreted as anxiety or worsening psychosis, leading to inappropriate dose increases that worsen the condition 1

• Overlooking EPS in atypical antipsychotics: Even atypical agents can cause EPS, especially at higher doses or in vulnerable patients 8

• Prolonged anticholinergic use: While effective for acute management, long-term anticholinergic use for EPS prophylaxis is controversial due to cognitive side effects 6

• Ignoring non-antipsychotic causes: Other medications including some antidepressants, antiemetics, and anticonvulsants can also cause EPS through similar mechanisms 2

Understanding that EPS primarily results from D2 receptor blockade in the nigrostriatal pathway helps guide both prevention and management strategies for these potentially serious medication side effects.