How do aripiprazole (Abilify) and brexpiprazole (Rexulti) differ?

Comment by InpharmD Researcher

While the differences in binding affinity suggest brexpiprazole may have a lower risk of akathisia and EPS compared to aripiprazole, there is a lack of real-world data comparing the adverse event profiles. Meta-analyses suggest a similar safety profile of both drugs, but one open-label study (Table 1) did show a higher incidence of akathisia with aripiprazole.

Background

Compared to aripiprazole (Abilify), brexpiprazole (Rexulti) has less intrinsic D2 activity (theoretically lower risk of akathisia and extrapyramidal symptoms), has higher potency at 5HT1a (may result in better antidepressant and anxiolytic effectiveness), and shows higher potency at 5HT2a (less likely to cause akathisia and insomnia). Meta-analyses show both aripiprazole and brexpiprazole to be linked with lower all-cause discontinuation rates compared to the placebo, but no significant difference was found between aripiprazole and brexpiprazole in this regard. Brexpiprazole showed a lower incidence of discontinuation due to adverse events compared to the placebo and was considered the best medication for this outcome. Aripiprazole 10-15mg, brexpiprazole 2mg, and brexpiprazole 4mg were linked to a higher incidence of weight gain (≥ 7%) compared to the placebo. Aripiprazole 10-15mg was associated with a lower incidence of diarrhea compared to the placebo and brexpiprazole 4mg. No significant differences were observed in other safety outcomes between aripiprazole, brexpiprazole, and placebo. Additionally, there was no considerable heterogeneity among the secondary outcomes. Brexpiprazole had the highest probability of being the best treatment for 11 out of 17 individual adverse event outcomes, including schizophrenia, agitation, anxiety, restlessness, and others. [1], [2], [3], [4]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

How does aripiprazole and brexpiprazole differ?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study
Design	Open-label, phase IIIb, exploratory, multicenter, flexible-dose study N= 97
Objective	To explore the effects of brexpiprazole and aripiprazole on efficacy, cognitive functioning, and safety in patients with acute schizophrenia
Study Groups	Brexpiprazole (n= 64) Aripiprazole (n= 33)
Inclusion Criteria	Adults aged 18-65 with DSM-IV-TR diagnosis of schizophrenia, PANSS total score ≥80, CGI-S score ≥4, and experiencing acute exacerbation of symptoms
Exclusion Criteria	First episode of schizophrenia, hospitalization >21 days for current episode, DSM-IV-TR Axis 1 diagnosis other than schizophrenia, or ≥20% improvement in PANSS score between screening and baseline
Methods	Participants received brexpiprazole (1-4 mg/day) or aripiprazole (10-20 mg/day) for 6 weeks. Dosages were adjusted based on clinical judgment.
Duration	6-week treatment phase with a 30-day follow-up
Outcome Measures	Primary: Change in PANSS total score Secondary: Change in CGI-S, SLOF, BIS-11, and Cogstate scores
Baseline Characteristics	Characteristic	Brexpiprazole (n = 64)	Aripiprazole (n = 33)
	Age, years	42.2 ± 10.1	42.1 ± 10.4
	Male	71.9%	69.7%
	Race White Black Asian Other	21.9% 75% 1.6% 1.6%	24.2% 72.7% 0 3%
	Weight, kg	89.9 ± 19.7	87.2 ± 18.3
	BMI, kg/m₂	30.2 ± 7.4	29.1 ± 6.2
Results		Brexpiprazole (n = 64)	Aripiprazole (n = 33)
	Mean change PANSS total score CGI-S score CGI-I score SLOF total score BIS-11 total score	-22.9 -1.6 2.5 7.7 -2.7	-19.4 -1.3 2.7 5.5 0.1
	Response rate	60.9%	48.5%
	Adverse events Akathesia Weight increase Headache Dyspepsia Dry Mouth Nausea Pain in extremity Constipation Diarrhea Back pain Sedation Muscle Spasm Toothache	9.4% 9.4% 7.8% 7.8% 7.8% 6.3% 6.3% 4.7% 4.7% 3.1% 0 0 0	21.2% 9.1% 12.1% 9.1% 6.1% 3% 3% 9.1% 6.1% 6.1% 6.1% 6.1% 6.1%
Study Author Conclusions	Brexpiprazole and aripiprazole both showed clinically relevant improvements in schizophrenia symptoms. Brexpiprazole had a lower incidence of akathisia and other EPS-related side effects compared to aripiprazole.
Critique	The study's open-label design may introduce bias. The small sample size limits generalizability. However, the study provides valuable insights into the efficacy and tolerability of brexpiprazole compared to aripiprazole.

References:

Citrome L, Ota A, Nagamizu K, Perry P, Weiller E, Baker RA. The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study. Int Clin Psychopharmacol. 2016;31(4):192-201. doi:10.1097/YIC.0000000000000123

Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies
Design	Three short-term, multicenter, randomized, double-blind, placebo-controlled studies Phase 2 study with 459 participants and two Phase 3 studies with a combined total of 1083 participants
Objective	To evaluate the efficacy of brexpiprazole in patients with acutely exacerbated schizophrenia
Study Groups	Phase 2: Brexpiprazole 0.25 mg (n=41), 1.0 ± 0.5 mg (n=88), 2.5 ± 0.5 mg (n=90), 5.0 ± 1 mg (n=92), placebo (n=93), aripiprazole 15 ± 5 mg (n=50) Phase 3: Brexpiprazole 0.25 mg (n=87), 1 mg (n=117), 2 mg (n=359), 4 mg (n=359), placebo (n=358).
Inclusion Criteria	Male and female patients aged 18–65 years with a DSM-IV-TR diagnosis of schizophrenia, requiring hospitalization for acute exacerbation
Exclusion Criteria	First episode of schizophrenia, DSM-IV-TR Axis I diagnosis other than schizophrenia, substance abuse or dependence in the previous 180 days, or a clinically significant medical condition
Methods	Phase 2: Participants were randomized to brexpiprazole (one of 4 dosings), aripiprazole, or placebo. Phase 3: Participants were randomized to brexpiprazole (one of 3 dosings) or placebo.
Duration	6 weeks for each study
Outcome Measures	Primary: Change in PANSS total score at week 6 Secondary: Change in CGI-S score, responder rates, and discontinuation rate due to lack of efficacy
Baseline Characteristics	Characteristic	Placebo	Brexpiprazole 0.25 mg	Brexpiprazole 1 ± 0.5 mg	Brexpiprazole 2 ± 0.5 mg	Brexpiprazole 5 ± 1 mg	Aripiprazole 15 ± 5 mg
	Age, years	38.8	40.8	39.2	37.4	39.3	40.8
	BMI, kg/m²	26.4	26.8	27.1	25.9	25.3	24.7
	Female	39.8%	34.1%	39.8%	33.3%	40.2%	32%
	PANSS total score	97.5	97.3	96.2	98.6	97.8	97.1
	CGI-S total score	5	7.8	4.8	5	5	4.9
Results		Placebo	Brexpiprazole 0.25 mg	Brexpiprazole 1 ± 0.5 mg	Brexpiprazole 2 ± 0.5 mg	Brexpiprazole 5 ± 1 mg	Aripiprazole 15 ± 5 mg
	PANSS total score change	-17.28	-12.41	-21.98	-19.00	-21.73	-20.97
	CGI-S total score change	-1.05	-0.63	-1.27	-1.12	-1.35	-1.30
	Responder rate	50.5%	41.5%	58%	46.7%	52.2%	60%
Adverse Events	Low incidence of EPS-related TEAEs and akathisia, low incidence of sedation and somnolence
Study Author Conclusions	Brexpiprazole 2 mg and 4 mg are effective for treating acute schizophrenia, with a favorable safety profile
Critique	These studies were well-designed, with a robust sample size and clear endpoints. However, the absence of an active comparator in Phase 3 trials is a limitation. The high placebo response in Phase 2 may have obscured treatment effects.

References:

Correll CU, Skuban A, Hobart M, et al. Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies [published correction appears in Schizophr Res. 2017 Dec;190:191-194. doi: 10.1016/j.schres.2017.02.030]. Schizophr Res. 2016;174(1-3):82-92. doi:10.1016/j.schres.2016.04.012