Can Vraylar (cariprazine) cause extrapyramidal symptoms (EPS)?

Can Vraylar Cause Extrapyramidal Symptoms?

Yes, Vraylar (cariprazine) can cause extrapyramidal symptoms (EPS), with akathisia being the most common manifestation, followed by other EPS such as acute dystonia, parkinsonism, and restlessness. 1, 2

Incidence and Risk Profile

The risk of EPS with cariprazine is dose-dependent, with higher doses carrying substantially greater risk:

• Acute EPS occurs in 4.5% of cariprazine-treated patients overall (3.8% at 1.5 mg/d; 5.1% at 3 mg/d) compared to 2.1% with placebo 1
• Akathisia is more common than other EPS, occurring in 7.6% overall (5.5% at 1.5 mg/d; 9.6% at 3 mg/d) versus 2.1% with placebo 1
• The number needed to harm (NNH) for EPS is 15 for cariprazine 1.5-3 mg/d versus placebo, and worsens to NNH 10 for 4.5-6 mg/d 2
• For akathisia specifically, NNH is 20 for lower doses (1.5-3 mg/d) and 12 for higher doses (4.5-6 mg/d) 2

Clinical Characteristics of Cariprazine-Related EPS

Most EPS events with cariprazine are mild to moderate in severity and occur early in treatment:

• Over 95% of akathisia and EPS events are mild to moderate in severity 1
• Most events occur during the first 3 weeks of cariprazine initiation or dose increase 1
• Median time to resolution after the last dose of cariprazine is approximately 1 week 1
• Fewer than 3% of patients discontinue treatment due to akathisia or EPS 1
• Rescue medication is needed in less than 3% of patients to manage akathisia/EPS events 1

Mechanism and Receptor Profile

Cariprazine's EPS risk relates to its unique pharmacology as a dopamine D3-preferring D2/D3 receptor partial agonist, with 10-fold higher affinity for D3 than D2 receptors 3. Despite this D3 preference, it still causes dopamine receptor blockade in nigrostriatal pathways sufficient to produce EPS 4, though the profile differs from typical antipsychotics 5.

Risk Mitigation Strategies

Conservative dosing and titration are essential to minimize EPS risk:

• Start at the lowest therapeutic dose of 1.5 mg/d, which is potentially therapeutic and carries lower EPS risk 2
• Use gradual titration when dose increases are necessary 1
• Consider that cariprazine has two active metabolites, with didesmethyl-cariprazine having a half-life of 1-3 weeks, meaning steady-state effects take time to develop 3
• Regular monitoring for early EPS signs is the preferred prevention strategy rather than prophylactic anticholinergics 4

Management When EPS Occurs

If EPS develops, follow this algorithmic approach:

• First strategy: Reduce the cariprazine dose when clinically feasible 4, 6
• For acute dystonia: Administer benztropine 1-2 mg IM/IV as first-line treatment 4
• For parkinsonism: Anticholinergic medications are helpful 6
• For akathisia: Beta-blockers and benzodiazepines may provide relief 6
• Second strategy: If dose reduction is insufficient, switch to an atypical antipsychotic with lower EPS risk such as olanzapine, quetiapine, or clozapine 4

Important Caveats

• Young males are at particularly elevated risk for acute dystonia 4
• Children and adolescents may be at higher overall risk for EPS than adults 6
• Akathisia is commonly misinterpreted as anxiety or psychotic agitation, which can lead to inappropriate dose increases rather than recognition of the medication-induced syndrome 4
• Anticholinergics should not be used routinely for preventing EPS but reserved for treatment of significant symptoms when dose reduction has failed 4