What are the differences between Brexpiprazole (Rexulti), Vraylar (Cariprazine), and Abilify (Aripiprazole)?

Differences Between Brexpiprazole (Rexulti), Cariprazine (Vraylar), and Aripiprazole (Abilify)

All three medications are dopamine D2/D3 receptor partial agonists that form a distinct pharmacological class, but they differ meaningfully in their receptor binding profiles, side effect profiles, and clinical applications—with brexpiprazole having the lowest akathisia risk, cariprazine having the highest D3 affinity and longest half-life, and aripiprazole being the prototype with intermediate properties. 1, 2

Pharmacological Distinctions

Receptor Binding Profiles

• Brexpiprazole has lower intrinsic dopamine D2 activity compared to aripiprazole, with higher potency at serotonin 5-HT1A and 5-HT2A receptors, plus significant noradrenergic alpha-1B and alpha-2C receptor activity 1, 3

• Cariprazine possesses the highest affinity for dopamine D3 receptors among all three agents and has the longest half-life, which distinguishes it pharmacokinetically 1

• Aripiprazole represents the prototype dopamine partial agonist with moderate D2 intrinsic activity, partial agonism at 5-HT1A receptors, and antagonism at 5-HT2A receptors 4

• All three share minimal alpha-adrenergic, anticholinergic, or antihistaminic activity, contributing to their favorable tolerability profiles 2

Side Effect Profile Differences

Akathisia Risk (Most Clinically Relevant Distinction)

• Brexpiprazole has the lowest akathisia risk among the three agents, likely due to its lower intrinsic D2 activity 1, 5

• Cariprazine has the highest akathisia risk, occurring in a small but notable proportion of patients, typically within the first few weeks of treatment 1

• Aripiprazole has intermediate akathisia risk, falling between brexpiprazole and cariprazine 1

• Akathisia with all three agents is generally low-to-moderate severity and occurs early in treatment 1

Weight Gain and Metabolic Effects

• Aripiprazole and cariprazine have low weight gain risk, making them preferred options when metabolic concerns are paramount 1, 2

• Brexpiprazole has moderate weight gain risk, more prominent than aripiprazole or cariprazine but still less than many other atypical antipsychotics 1, 5

• All three have very low risk of metabolic syndrome compared to dopamine D2 antagonists 2

Prolactin and Sexual Function

• All three agents have low risk for hyperprolactinemia due to their partial dopamine agonist activity 1, 2

• Prolactin levels may actually decrease in patients with elevated baseline levels when starting any of these medications 1

• Sexual dysfunction risk is likely low across all three agents 1

Sedation and Insomnia

• Brexpiprazole causes less sedation than aripiprazole but more than cariprazine 5

• All three have low overall sedation risk and may cause insomnia at treatment initiation 1, 2

Clinical Applications and Dosing

FDA-Approved Indications

• Aripiprazole is approved for schizophrenia, bipolar mania, and as monotherapy or adjunct for major depressive disorder 4

• Brexpiprazole is approved for schizophrenia and as adjunctive treatment in major depressive disorder 3, 5

• Cariprazine is approved for schizophrenia and bipolar disorder (specific indications vary)

Dosing Strategies

• Brexpiprazole: Target dose 2-4 mg/day for schizophrenia, 2 mg/day for depression augmentation; requires titration over 1-2 weeks 3, 5

• Aripiprazole: Typically dosed at recommended levels with rapid onset of action within one week 4

• All three are effective with once-daily dosing due to long duration of action 3, 2

• Dose adjustments needed for hepatic/renal dysfunction and poor CYP2D6 metabolizers with brexpiprazole 5

Efficacy Considerations

Schizophrenia Treatment

• Brexpiprazole shows number needed to treat (NNT) vs placebo of 6-15 for response in acute schizophrenia and NNT of 4 for maintenance 5

• Aripiprazole demonstrates effectiveness for positive and negative symptoms with rapid onset within one week 4

• All three are effective antipsychotics with continued efficacy in long-term studies 4, 2

Depression Augmentation

• Brexpiprazole has NNT of 12 for response and 17-31 for remission vs placebo in major depression 5

• Both aripiprazole and brexpiprazole have demonstrated efficacy as adjunctive treatments for major depressive disorder 3, 4

Critical Safety Considerations

Impulse Control Disorders

• Aripiprazole has been implicated in pathological gambling and other impulse control behaviors, likely due to partial dopamine agonist activity 1

• No reports of impulse control disorders have emerged with brexpiprazole or cariprazine to date 1

Discontinuation Rates

• In schizophrenia trials, brexpiprazole showed lower discontinuation rates due to adverse effects compared to placebo (7.1%-9.2% vs 14.7%) 5

• In depression studies, brexpiprazole discontinuation rates were higher than placebo (1.3%-3.5% vs 0-1.4%) and appeared dose-dependent 5

Common Pitfalls to Avoid

• Avoid rapid titration of brexpiprazole—it requires 1-2 weeks to reach target dose to minimize akathisia and other side effects 3, 5

• Do not assume equivalent akathisia risk—cariprazine has the highest risk, which may lead to non-adherence if not anticipated and managed 1

• Monitor for impulse control disorders with aripiprazole, particularly pathological gambling, which has not been reported with the newer agents 1

• Consider weight gain differences when selecting agents—brexpiprazole causes more weight gain than aripiprazole or cariprazine, which matters for long-term metabolic health 1, 5

• Recognize the long half-life of cariprazine—this affects both steady-state achievement and washout periods 1