What are extrapyramidal side effects?

What Are Extrapyramidal Side Effects?

Extrapyramidal side effects (EPS) are a group of drug-induced movement disorders caused by dopamine receptor blockade in the basal ganglia, most commonly occurring with antipsychotic medications but also with certain antiemetics and other dopamine-blocking agents. 1, 2

Types of Extrapyramidal Symptoms

EPS encompass several distinct clinical syndromes that differ in timing, presentation, and management:

Acute Dystonia

• Sudden, involuntary spastic contractions of distinct muscle groups, typically affecting the neck, eyes (oculogyric crisis), or torso 1, 2
• Usually occurs within the first 3-5 days after starting antipsychotic therapy or increasing the dose 1, 3
• Can be life-threatening in cases of laryngospasm 1, 4
• Young males are at highest risk for dystonic reactions 1, 5
• Responds well to anticholinergic medications (benztropine 1-2 mg IM/IV) or antihistaminic agents 1, 5

Drug-Induced Parkinsonism

• Mimics idiopathic Parkinson's disease with bradykinesia (slowed movement), tremors, and muscle rigidity 1, 2
• Generally appears within the first 3 months of antipsychotic treatment 1, 3
• Results from direct dopamine D2 receptor blockade in the nigrostriatal pathways 5
• Treated with anticholinergic agents or mild dopaminergic agents like amantadine 1
• Important pitfall: Can be difficult to distinguish from negative symptoms of schizophrenia or, in severe cases, catatonia 1

Akathisia

• Subjective sense of severe restlessness with objective motor agitation, frequently manifesting as pacing or inability to sit still 1, 4
• Appears days to weeks after antipsychotic exposure begins 3
• Commonly misinterpreted as psychotic agitation or anxiety, leading to inappropriate dose increases 1, 5
• Major cause of medication noncompliance 1
• Difficult to treat: First-line approach is dose reduction when feasible; beta-blockers (especially propranolol) and benzodiazepines may provide relief, while anticholinergics are inconsistently helpful 1, 3

Tardive Dyskinesia

• Involuntary choreic or athetoid movements, typically in the orofacial region (tongue protrusion, lip smacking, chewing movements) but can affect any body part 1, 4
• Associated with long-term antipsychotic use 1
• Represents a major public health concern with clinical and medicolegal implications 1
• Risk is approximately 5% per year in young patients 5
• Critical distinction: Withdrawal dyskinesia may occur with sudden or gradual discontinuation and is usually temporary, unlike true tardive dyskinesia 1

Tardive Dystonia

• Sustained dystonic postures associated with long-term antipsychotic use 1
• Can be quite disabling and often coexists with tardive dyskinesia 1
• Managed with the same strategies as tardive dyskinesia: dose reduction or medication switching 1

Medications That Cause EPS

High-Risk Medications

• High-potency typical antipsychotics (haloperidol, fluphenazine, droperidol) carry the highest risk due to strong D2 receptor blockade 1, 5
• Antiemetics: Metoclopramide and phenothiazines (prochlorperazine) have higher EPS rates than alternatives like cinitapride 2
• Risperidone has dose-dependent EPS risk, particularly above 2 mg/day 4, 5

Lower-Risk Medications

• Atypical antipsychotics generally have lower EPS liability: clozapine and quetiapine have the lowest risk, followed by olanzapine 5, 6
• Low-potency typical antipsychotics (chlorpromazine, thioridazine) cause more sedation and anticholinergic effects but fewer EPS 1, 4

Non-Antipsychotic Causes

• Certain antidepressants, lithium, anticonvulsants, and rarely oral contraceptives can cause EPS indistinguishable from neuroleptic-induced symptoms 7

Risk Factors for Developing EPS

• Age: Children, adolescents, and elderly patients are at higher risk 1, 5
• Gender: Male gender increases risk, particularly for acute dystonia 1, 5
• Medication factors: High-potency agents, rapid dose escalation, and higher doses increase risk 5
• Concurrent medications: Polypharmacy with psychotropic agents elevates risk 2
• Substance use: Methamphetamine use disorders significantly increase EPS risk (OR 4.01), with a dose-response relationship to antipsychotic dosage 8
• Other factors: Dehydration, physical exhaustion, and preexisting brain disease 2

Prevention and Management Strategies

Medication Selection

• Choose atypical antipsychotics with lower EPS profiles (clozapine, quetiapine, olanzapine) as first-line agents when appropriate 5, 6
• For risperidone, use the lowest effective dose (typically 2-4 mg/day in adults) and avoid exceeding 2 mg/day in elderly patients 5
• In first-episode psychosis, limit doses to maximum 4-6 mg haloperidol equivalent 5

Dosing Strategy

• Start low and titrate slowly, increasing doses only at widely spaced intervals (14-21 days after initial titration) 5
• Avoid rapid dose escalation, which increases EPS risk 5

Monitoring

• Regular monitoring for early EPS signs is essential rather than routine prophylactic anticholinergics 4, 5
• Use standardized scales: Abnormal Involuntary Movement Scale (AIMS) at least every 3-6 months after starting therapy 4

Treatment of Acute EPS

For acute dystonia:

• Benztropine 1-2 mg IM/IV is first-line treatment 5
• Maintain anticholinergics even after antipsychotic discontinuation to prevent delayed symptom emergence 5

For parkinsonism:

• First strategy: Reduce antipsychotic dose 5
• Second strategy: Switch to atypical antipsychotic with lower EPS risk (olanzapine, quetiapine, clozapine) 5
• Consider anticholinergic agents if dose reduction fails 1

For akathisia:

• Dose reduction is preferred when clinically feasible 1
• Lipophilic beta-blockers (propranolol, metoprolol) are most effective 3
• Benzodiazepines may provide relief 1

Prophylactic Anticholinergics

• Not recommended routinely but may be considered in high-risk patients (young males, history of dystonic reactions, paranoid patients where compliance is critical) 1, 5
• Reevaluate need after acute phase as many patients no longer require them during long-term therapy 1

Important Clinical Pitfalls

• Anticholinergic medications can cause delirium, drowsiness, and paradoxical agitation, particularly in patients with anticholinergic or sympathomimetic drug ingestions 5
• Akathisia is frequently misdiagnosed as anxiety or psychotic agitation, leading to inappropriate dose increases that worsen the problem 1, 5
• EPS can confound mental state assessment due to symptom overlap with psychotic illness 9
• Patients with methamphetamine use disorders require particularly careful dose titration due to disproportionately higher EPS risk as antipsychotic dosage increases 8
• For metoclopramide-induced EPS, immediate drug withdrawal is recommended 5