What are the key differences between cariprazine and other atypical antipsychotics?

From the Guidelines

Cariprazine (Vraylar) differs from other atypical antipsychotics primarily through its unique receptor binding profile, acting as a partial agonist at dopamine D3 receptors with higher affinity than for D2 receptors. This distinguishes it from medications like risperidone, olanzapine, or quetiapine, which primarily block D2 receptors 1. Cariprazine is FDA-approved for schizophrenia and bipolar disorder, with emerging evidence for adjunctive use in major depression. Its long half-life means it takes longer to reach steady state and longer to clear after discontinuation, requiring gradual dose adjustments. Some key points to consider when prescribing cariprazine include:

• Metabolic advantages with lower risk of weight gain, diabetes, and lipid abnormalities compared to olanzapine or quetiapine, and less prolactin elevation than risperidone 1
• Less sedation than quetiapine or olanzapine but higher rates of akathisia (restlessness) than some alternatives
• The medication is taken once daily without regard to food but is relatively expensive as a newer agent with limited generic availability
• Its D3 preference may provide better benefits for negative symptoms of schizophrenia and cognitive symptoms, though it requires careful monitoring for extrapyramidal symptoms, especially during initiation 1 When choosing an antipsychotic medication, the decision should be based on the agent’s relative potency, potential side effects, and the patient’s history of medication response, as individual responses to different antipsychotics are variable 1.

From the FDA Drug Label

The mechanism of action of cariprazine is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity

The key differences between cariprazine and other atypical antipsychotics are:

• Unique receptor binding profile: Cariprazine has a distinct receptor binding profile, with partial agonist activity at dopamine D2 and D3 receptors, and antagonist activity at serotonin 5-HT2A receptors.
• High binding affinity: Cariprazine has high binding affinity for dopamine D2 and D3 receptors, and moderate to high binding affinity for serotonin 5-HT2A and 5-HT2B receptors.
• Pharmacologically active metabolites: Cariprazine has two major active metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which are pharmacologically equipotent to cariprazine 2

From the Research

Key Differences

• Cariprazine is a dopamine D3- and D2-receptor partial agonist, with tenfold higher affinity for D3 receptors than for D2 receptors 3
• Cariprazine has a unique pharmacology that suggests potential advantages against negative symptoms, and cognitive and functional impairment, which are challenging to treat 4
• Cariprazine is metabolized in two steps by CYP3A4 to didesmethyl-cariprazine (DDCAR), with a long half-life of 1-3 weeks 3

Efficacy and Safety

• Cariprazine has been found to be effective for the treatment of schizophrenia, with a number needed to treat vs placebo for response of ten for the approved dose range of 1.5-6 mg/day 3
• Cariprazine has also been found to be effective for the maintenance treatment of schizophrenia, delaying time to relapse when compared with placebo (HR 0.45) 3
• Cariprazine is generally safe and well tolerated, with a favorable weight and metabolic profile, and no increase in prolactin levels or prolongation of the electrocardiographic QT interval 4, 3, 5, 6

Comparison to Other Antipsychotics

• Cariprazine differs from other antipsychotics in its mechanism of action, with a preference for D3 receptors over D2 receptors 3
• Cariprazine has been compared to risperidone in a 26-week randomized clinical trial, with cariprazine showing superiority for the treatment of predominantly negative symptoms in patients with schizophrenia 3
• Cariprazine has a unique pharmacology that may offer broad-spectrum efficacy advantages for patients with schizophrenia, including effects against difficult-to-treat negative and cognitive symptoms, as well as functional improvements 4