Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.12
In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.
Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.
EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.
Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:
- minimal effect on prolactin
- relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).
Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.1
The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.1
Other key aspects of dosing to keep in mind:
- Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
- Administering the drug with food slightly delays, but does not affect, the extent of absorption.
- Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
- Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.1
- Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4
Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.1
Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.1
In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.