Aripiprazole, brexpiprazole, and cariprazine: Not all the same

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

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