What are the extrapyramidal side effects of dopamine‑blocking agents and how should each be treated?

Extrapyramidal Side Effects of Dopamine-Blocking Agents

Types and Immediate Treatment

For acute dystonia, immediately administer benztropine 1-2 mg IM/IV or diphenhydramine 12.5-25 mg IM/IV, which provides relief within minutes; for drug-induced parkinsonism, reduce the antipsychotic dose first, then switch to olanzapine, quetiapine, or clozapine before adding anticholinergics; for akathisia, reduce the dose and trial propranolol or metoprolol as first-line pharmacological treatment. 1

Acute Dystonia

Clinical Presentation:

• Sudden spastic contractions of distinct muscle groups (neck, eyes with oculogyric crisis, or torso) 1, 2
• Typically occurs within the first few days of treatment 1, 2
• Can be life-threatening, particularly with laryngospasm 1
• Young males represent the highest-risk group 1, 2

Treatment Algorithm:

1. Immediate pharmacological intervention required 1
2. First-line: Benztropine 1-2 mg IM/IV for rapid relief (improvement within minutes) 1, 2
3. Alternative: Diphenhydramine 12.5-25 mg IM/IV provides equivalent rapid relief 1, 2
4. Continue anticholinergic medication even after antipsychotic discontinuation to prevent delayed symptom emergence 2

Drug-Induced Parkinsonism

Clinical Presentation:

• Bradykinesia, tremors, and rigidity mimicking idiopathic Parkinson's disease 1, 2
• Direct result of dopamine D2 receptor blockade 2
• Generally appears within the first three months 3

Treatment Hierarchy (in order):

1. First strategy: Reduce the antipsychotic dose if clinically feasible 1, 2
2. Second strategy: Switch to olanzapine, quetiapine, or clozapine (substantially lower EPS risk) 1, 2
3. Third strategy: Add anticholinergic agents only after dose reduction and switching strategies have failed 1, 2
4. Early diagnosis and rapid antipsychotic withdrawal improves possibility of complete recovery 1

Akathisia

Clinical Presentation:

• Subjective feeling of restlessness and physical agitation 1, 2
• Frequently misinterpreted as psychotic agitation or anxiety, leading to inappropriate dose escalation 1, 2
• Most difficult EPS to treat 1
• Appears days to weeks after antipsychotic exposure 3

Treatment Algorithm:

1. First strategy: Lower the antipsychotic dose if clinically feasible 1, 2
2. Second strategy: Lipophilic beta-blockers (propranolol or metoprolol) are the most effective pharmacological treatments 1, 3
3. Third strategy: Anticholinergic agents may provide relief but are less consistently effective than for dystonia or parkinsonism 2
4. Alternative: Benzodiazepines can be considered 3

Tardive Dyskinesia

Clinical Presentation:

• Involuntary choreiform or athetoid movements, typically of the orofacial region, but can affect any body part 2
• Associated with long-term antipsychotic use 2
• Occurs in approximately 5% of young patients per year 1, 2
• More common with typical antipsychotics 1

Management:

• Monitor every 3-6 months using a standardized scale during long-term antipsychotic therapy 1, 2
• Use the same strategies as for tardive dystonia: reduce dose or switch medication 2
• Maintain antipsychotic only if patient is in complete remission and medication change would precipitate relapse 2

Medication Selection to Minimize EPS Risk

Lowest EPS Risk:

• Olanzapine, quetiapine, and clozapine have the lowest EPS risk among atypical antipsychotics 1, 2
• Clozapine is most effective for treatment-resistant symptoms but requires blood monitoring for agranulocytosis 2

Dose-Dependent Risk:

• Risperidone carries dose-dependent EPS risk that increases significantly above 2 mg/day in elderly/dementia patients and above 4-6 mg/day in general populations 1, 2
• Haloperidol and other high-potency typical antipsychotics produce significantly more EPS due to strong dopamine D2 receptor blockade 1, 2

First-Episode Psychosis Dosing:

• Use maximum 4-6 mg haloperidol equivalent 2
• Increase doses only at widely spaced intervals (14-21 days after initial titration) if response is inadequate 2

Critical Anticholinergic Medication Cautions

Adverse Effects:

• Can cause delirium, drowsiness, and paradoxical agitation, particularly in older adults 1, 2
• Exercise extreme caution in elderly patients due to oversedation, confusion, and paradoxical agitation risk 1, 2

Contraindications for Diphenhydramine:

• Avoid in patients with glaucoma, benign prostatic hypertrophy, ischemic heart disease, or hypertension 1, 2
• Can paradoxically exacerbate agitation in patients with anticholinergic or sympathomimetic drug ingestions 1, 2

Prophylaxis Considerations:

• Anticholinergics should not be used routinely for preventing EPS 2
• Reserve prophylactic antiparkinsonian agents for truly high-risk patients: young males, history of dystonic reactions, or paranoid patients where compliance is an issue 2
• Regular monitoring for early EPS signs is the preferred prevention strategy rather than prophylactic anticholinergics 1, 2
• Reevaluate need for antiparkinsonian agents after the acute phase or if antipsychotic doses are lowered, as many patients no longer need them during long-term therapy 2

Special Populations

Children and Adolescents:

• Higher risk for EPS than adults, particularly acute dystonia in young males 1, 2
• Use particularly cautious dosing despite some studies showing comparable EPS rates to placebo in controlled trials 1, 2
• Young males represent the highest-risk group for acute dystonia, typically occurring within the first few days of treatment 1, 2

Elderly Patients:

• Increased risk of anticholinergic adverse effects 1, 2
• Lower risperidone threshold for EPS (above 2 mg/day) 1, 2

Neuroleptic Malignant Syndrome

Treatment:

• Bromocriptine and anticholinergic agents were helpful in case reports, but dantrolene was not effective in pediatric cases 4, 2
• Further study is needed as reports are not definitive 4