Cariprazine and Akathisia, Restlessness, and Extrapyramidal Symptoms in Patients With Bipolar Depression

Abstract Background Akathisia is a neuropsychiatric syndrome that is commonly related to the use of dopamine antagonist/partial agonists. The characteristics of cariprazine-related akathisia, restlessness, and extrapyramidal symptoms (EPS) were investigated in patients with bipolar I depression. Methods Akathisia-related data from 3 fixed-dose clinical studies of cariprazine 1.5 mg/d and 3 mg/d in bipolar depression were evaluated in pooled post hoc analyses. Outcomes related to treatment-emergent adverse events (TEAEs) included incidence, time to onset, time to resolution, severity, discontinuations, and rescue medication use. Results The incidence of akathisia was 7.6% for overall cariprazine (1.5 mg/d=5.5%; 3 mg/d=9.6%) and 2.1% for placebo; acute EPS occurred in 4.5% of cariprazine-treated (1.5 mg/d=3.8%; 3 mg/d=5.1%) and 2.1% of placebo-treated patients. Findings were similar for restlessness. Most TEAEs were mild/moderate (>95%), occurred during the first 3 weeks of cariprazine initiation or dose increase, and resulted in few discontinuations ( Limitations Post hoc analyses; no active comparator. Conclusions In patients with bipolar depression, the incidence of cariprazine-related akathisia was higher than acute EPS or restlessness, with lower cariprazine doses associated with lower incidences of events. Akathisia and EPS TEAEs occurred early in treatment and were mild/moderate in severity. Few patients with akathisia or acute EPS discontinued treatment, suggesting that TEAEs were well tolerated. Cariprazine-related akathisia and EPS can be minimized with conservative dosing and titration strategies. Trial Registration ClinicalTrials.gov Identifiers: NCT01396447, NCT02670538, NCT02670551