Does Aripiprazole (Abilify) cause Extrapyramidal Symptoms (EPS)?

Does Aripiprazole Cause Extrapyramidal Symptoms?

Yes, aripiprazole does cause extrapyramidal symptoms (EPS), though at lower rates than first-generation antipsychotics and with a dose-dependent relationship that becomes more pronounced at higher doses. 1, 2

Incidence and Risk Profile

Adult Populations

• In short-term placebo-controlled trials of adults with schizophrenia, EPS-related events (excluding akathisia) occurred in 13% of aripiprazole patients versus 12% on placebo, while akathisia occurred in 8% versus 4% on placebo 2
• The most commonly observed adverse reaction with aripiprazole that exceeded placebo by at least two-fold was akathisia (8% vs 4%) 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 substantially after 4 or more prescriptions (OR 8.64) 3

Pediatric Populations (13-17 years)

• Adolescents experience significantly higher EPS rates than adults: 25% versus 7% on placebo for general EPS-related events, and 9% versus 6% for akathisia 2
• Commonly observed adverse reactions in adolescents (≥5% and at least twice placebo rate) included extrapyramidal disorder, somnolence, and tremor 2

Dose-Response Relationship

The risk of EPS increases with higher doses, particularly at 30 mg/day: 2

• In pediatric trials, extrapyramidal disorder occurred in 5% on placebo, 13% on 10 mg, and 21.6% on 30 mg 2
• Tremor showed similar escalation: 2% on placebo, 2% on 10 mg, and 11.8% on 30 mg 2
• In adults, somnolence (including sedation) was the only adverse reaction showing clear dose-response, most prominent at 30 mg (12.6% vs 7.1% placebo) 2

Comparative Risk Among Antipsychotics

Aripiprazole occupies a middle position in the EPS risk hierarchy: 4

• From lowest to highest EPS risk: Quetiapine < Aripiprazole < Olanzapine < Risperidone < typical antipsychotics (like haloperidol) 4
• Aripiprazole causes zero mean QT prolongation (0 ms), making it safer than many alternatives for cardiac considerations 5
• The American Academy of Neurology reports that aripiprazole is less likely to cause EPS than first-generation antipsychotics, though risk increases at higher doses 1

Clinical Manifestations

Types of EPS with Aripiprazole

Acute dystonia can occur after first few doses, involving involuntary motor tics or spasms of face, extraocular muscles, neck, back, and limbs 5

Akathisia presents as subjective restlessness, typically within the first few days of therapy 5

• In late-life depression trials, 26.7% of aripiprazole patients developed akathisia versus 12.2% on placebo 6
• Greater baseline depression severity predicted treatment-emergent akathisia 6
• Most akathisia cases were mild and responded to dose reduction 6

Drug-induced Parkinsonism may develop, characterized by tremor, rigidity, and bradykinesia 5

Tardive dyskinesia occurred in only 0.2% of aripiprazole patients in short-term trials, similar to placebo (0.2%) 7

Important Clinical Caveats

Objective vs. Subjective Measures

A critical discrepancy exists between reported and objectively measured EPS: 2

• While subjective reports showed increased EPS rates, objective measurements using Simpson Angus Rating Scale and Barnes Akathisia Scale generally did not show differences from placebo in adult trials 2
• The exception was the Barnes Akathisia Scale in adults (aripiprazole 0.08 vs placebo -0.05) and Simpson Angus Scale in adolescents (0.24 vs -0.29) 2

Special Populations at Higher Risk

Elderly patients, poor CYP2D6 metabolizers, and those with hepatic impairment require lower doses to minimize EPS risk 1, 8

Males and younger age groups have elevated risk of acute dystonia, which occurs more frequently with high-potency first-generation antipsychotics but can still occur with aripiprazole 2

Overdose Considerations

EPS can occur with aripiprazole overdose: A case report documented EPS development after ingestion of 200 mg, which resolved with biperiden administration 9

Management Approach

When EPS develops with aripiprazole: 1, 6

• First-line intervention is dose reduction, which typically resolves akathisia and other EPS symptoms 1, 6
• Consider switching to quetiapine if EPS persists, as it has the lowest EPS risk among antipsychotics 4
• Anticholinergic medications like benztropine should be reserved for treatment after EPS develops, not used prophylactically 4

For combination therapy scenarios, lower doses of aripiprazole may maintain efficacy while reducing EPS risk 1