Aripiprazole and Extrapyramidal Symptoms
Yes, aripiprazole can cause extrapyramidal symptoms (EPS), though it carries a lower risk compared to typical antipsychotics and some other atypical agents. 1
Risk Profile and Clinical Evidence
Aripiprazole is classified as "less likely to cause EPSEs" according to major clinical practice guidelines, distinguishing it from high-potency typical antipsychotics like haloperidol and even some second-generation agents. 1 The 2025 INTEGRATE guidelines specifically note aripiprazole's favorable EPS profile when recommending it for negative symptoms in schizophrenia. 1
However, the FDA drug label clearly documents that EPS does occur with aripiprazole:
Incidence in Clinical Trials
In adult schizophrenia trials:
- EPS-related events (excluding akathisia): 13% with aripiprazole vs. 12% with placebo 2
- Akathisia specifically: 8% with aripiprazole vs. 4% with placebo 2
- Akathisia was the only commonly observed adverse reaction (≥5% and at least twice placebo rate) 2
In adolescent schizophrenia trials (ages 13-17):
- EPS-related events (excluding akathisia): 25% with aripiprazole vs. 7% with placebo 2
- Akathisia: 9% with aripiprazole vs. 6% with placebo 2
- Extrapyramidal disorder, somnolence, and tremor were the most common adverse reactions at rates twice that of placebo 2
Dose-Response Relationship
EPS risk increases with higher doses of aripiprazole. 2 In pediatric patients, extrapyramidal disorder showed clear dose-dependency:
- Placebo: 5%
- 10 mg: 13%
- 30 mg: 21.6% 2
Similarly, tremor increased from 2% (placebo) to 2% (10 mg) to 11.8% (30 mg). 2
Types of EPS Associated with Aripiprazole
Akathisia is the most common EPS manifestation with aripiprazole, occurring in approximately 8-10% of adult patients. 2 A large pharmacoepidemiologic study found the odds ratio for EPS among aripiprazole users was 5.38 (95% CI: 3.03-9.57) compared to non-users, with risk increasing to 8.64 (95% CI: 2.63-28.38) in those receiving more than 4 prescriptions. 3
Other EPS manifestations include:
- Tremor (5% in adults, 9% in adolescents) 2
- Dystonia (2% in adolescents) 2
- Drug-induced parkinsonism 4
- Dyskinesia (OR 8.50; 95% CI: 8.53-2.27-31.97 vs. non-users) 3
Important Clinical Considerations
EPS can occur even at low doses. A case report documented extrapyramidal symptoms in an 11-year-old child receiving only 5 mg of aripiprazole, emphasizing the need for surveillance even at minimal dosing. 5
The mechanism may involve both dopaminergic and cholinergic pathways. Beyond its partial D2 agonist activity, aripiprazole inhibits acetylcholinesterase at clinically achievable concentrations (≥10⁻⁶ mol/L), potentially augmenting cholinergic effects and contributing to EPS. 6
Most akathisia cases are mild and respond to dose reduction. In older adults with depression receiving aripiprazole augmentation, 26.7% developed akathisia, but most improved over time, particularly with dosage adjustments. 4 Greater baseline depression severity predicted higher akathisia risk. 4
Clinical Management Approach
When prescribing aripiprazole:
- Start with the lowest effective dose and avoid rapid escalation 7
- Monitor closely for EPS, particularly in adolescents (who show 3-fold higher rates than adults), males, and those with greater symptom severity 7, 2, 4
- Consider dose reduction as first-line management if EPS develops 4
- Reserve anticholinergic medications for significant symptoms when dose reduction fails, as they carry risks of delirium and cognitive impairment 7
Aripiprazole remains a preferred option when EPS risk is a concern compared to typical antipsychotics and higher-risk atypical agents, but clinicians must remain vigilant for these adverse effects, particularly at higher doses and in vulnerable populations. 1