Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.
Clinical implications
Despite numerous developments in pharmacotherapeutics, people with schizophrenia or bipolar disorder continue to struggle with residual symptoms or endure treatments that produce adverse effects (AEs). In particular, metabolic issues, sedation, and cognitive impairment plague many current treatment options for these disorders.
Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor3-5 (Table 2).
Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.1,6-8
Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.9-12
Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.13
Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.
How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:
- decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
- simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
- exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
- simultaneously
Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.14In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.
Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.
Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.1