A Brief Review of Cariprazine

Cariprazine functions as a partial agonist of dopaminergic D₂ and D₃ receptors and serotonergic 5-HT_1A receptors (1). Cariprazine also has moderate antagonistic properties at serotonergic 5-HT_2A and 5-HT_2B receptors, as well as histaminergic H₁ receptors (2). Cariprazine’s most salient feature is its preference for D₃ receptors; its D₃ binding affinity is higher than dopamine’s affinity for this receptor (3). This means that at physiological doses, cariprazine can cause a unique D₃ blockade, unlike other second-generation antipsychotics whose D₃ -binding properties are reversible by dopamine (4). D₃ receptors can be found in different areas of the brain, such as the hypothalamus, limbic areas, the ventral tegmental area, and the cerebral cortex (5). D₃ partial agonism in the cortex may improve negative symptoms and cognitive deficits among patients with schizophrenia (2). Although the mechanism is largely unclear, it has been hypothesized that there is an overexpression of D₃ receptors on dopaminergic neurons (autoreceptors) projecting from the ventral tegmental area to the prefrontal cortex leading to dopaminergic hypofunction (2). The partial agonism effect of cariprazine may therefore reverse this inhibition and thus lead to normalization of dopamine release within the prefrontal cortex. The activity of cariprazine on 5-HT_1A and 5-HT_2A receptors helps to improve psychotic or manic symptoms, as well as lower the occurrence of extrapyramidal symptoms (2). Cariprazine exhibits a greater binding affinity for D₂ receptors than dopamine; however, this is a pharmacological property shared with other commonly used antipsychotics (4).

Cariprazine is available in four doses: 1.5 mg, 3 mg, 4.5 mg, and 6 mg. Cariprazine is extensively metabolized by the liver, mainly by CYP3A4 and to a lesser extent by CYP2D6. Administration of a single dose of cariprazine results in peak plasma concentration within 3–6 hours (6). After multiple doses of cariprazine, the mean systemic concentration reaches steady-state levels after 1–2 weeks. There is no effect of food on serum concentrations (6).

Given that cariprazine is metabolized by CYP3A4, specific considerations must be taken when patients are co-administered CYP3A4 inhibitors and inducers. If taken with a CYP3A4 inhibitor, cariprazine’s active metabolite concentrations will be increased. For patients on a stable dose of cariprazine who are initiating a strong CYP3A4 inhibitor, the dose of cariprazine should be decreased by half (6). Because there has been little research on potential toxicity for patients who are concomitantly taking cariprazine and CYP3A4 inducers, taking them together is recommended against.

In clinical trials for patients with schizophrenia, the most frequent adverse reactions were extrapyramidal symptoms and akathisia (6). In clinical trials for patients with manic or mixed episodes associated with bipolar I disorder, the most frequent adverse reactions were extrapyramidal symptoms, headaches, and akathisia, where 2% of patients discontinued treatment because of akathisia (6). Extrapyramidal symptom events included parkinsonism, restlessness, dystonias, and musculoskeletal stiffness. Other adverse reactions noted were insomnia, weight gain, nausea, and constipation (10). A list of adverse reactions described in clinical trials is presented in Table 1.

During clinical trials, cariprazine caused no clinically meaningful changes in blood pressure (6). There was also a low incidence of cataracts as well as gastrointestinal, hepatobiliary, musculoskeletal, psychiatric, renal, and skin disorders (6). Despite reports of patient weight gain during these trials, no changes in lipid or metabolic serum chemistry were clinically meaningful, although there was a statistically significant increase in triglycerides with cariprazine in the 3–6 mg/day dose range (10). Overall, there were also no statistically significant changes in prolactin levels in all dose groups (10) and an increase in mean creatinine phosphokinase levels among 4% of patients, with no associated changes in renal function (6).

Special considerations must be taken for pregnant patients, because there are not enough available data regarding cariprazine-associated risks of birth defects or miscarriages among humans (6). Animal studies have shown that although cariprazine may be associated with malformations and developmental delays in rat models, it poses no teratogenic risk in rabbit models (6). Reported neonatal adverse reactions associated with the general use of antipsychotics include extrapyramidal or withdrawal symptoms during the third trimester of pregnancy. Data are insufficient to determine cariprazine’s safety during breastfeeding and in the pediatric population. Previous studies have shown greater risk of death among elderly patients, and therefore the use of cariprazine for treatment of dementia-related psychosis is not approved at this time (16).

Cariprazine’s unique pharmacological feature of being a partial agonist with an affinity for D₃ receptors that surpasses that of endogenous dopamine makes it a potent and efficacious second-generation antipsychotic. It has shown superior efficacy in the treatment of schizophrenia and manic and mixed episodes of bipolar I disorder. It is approved for the treatment of schizophrenia, manic and mixed episodes of bipolar I disorder, and bipolar depression and as adjunctive treatment for unipolar depression. Despite some side effects, such as akathisia and extrapyramidal symptoms, cariprazine has shown a positive safety and tolerance profile that may contribute to treatment adherence among patients with the aforementioned psychiatric conditions.