Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy?

Dopamine receptor partial agonists (DRPAs; aripiprazole, brexpiprazole, and cariprazine) constitute a novel class of antipsychotics. Although they share a similar mechanism of action, DRPAs differ in their pharmacodynamics, pharmacokinetics, drug interactions, or safety and tolerability. The antipsychotic efficacy of all three drugs was established in several placebo-controlled randomized trials (RCTs) in schizophrenia, both acute phase and relapse prevention. In addition, each of the DRPA agents has been tested in other psychiatric disorders, including bipolar disorder or major depression. However, a few studies have examined their comparative clinical efficacy. There are no head-to-head comparisons between aripiprazole, brexpiprazole, or cariprazine. In two acute schizophrenia RCTs of cariprazine and brexpiprazole, aripiprazole was used as an indirect comparator to control for study sensitivity. To assess potential differences in the efficacy of DRPAs, we reviewed data from controlled trials, systematic reviews, and meta-analyses. Our results showed that the acute antipsychotic effects of DRPAs, as measured by the number needed to treat, are comparable. The three agents were superior to placebo in acute treatment, and cariprazine was found to be effective in the reduction of primary negative symptoms of schizophrenia. In the therapy of bipolar disorder, aripiprazole and cariprazine showed antimanic efficacy, cariprazine was also effective in the management of bipolar depression, and aripiprazole was effective for relapse prevention. The addon administration of aripiprazole or brexpiprazole reduced symptoms of major depression. Aripiprazole can control acute agitation associated with psychosis or bipolar disorder; brexpiprazole showed the potential to manage agitation in dementia patients. Aripiprazole has also established evidence of efficacy in children and adolescents and other conditions: OCD, tic disorders, and autism spectrum disorder. Our review of published data suggests that in terms of clinical efficacy, DRPAs are a heterogeneous group, with each drug possessing its own therapeutic benefits.


INTRODUCTION
Antipsychotic drugs represent the mainstay of schizophrenia treatment (1). They all share a common mechanism of action: antagonism at postsynaptic dopamine D 2 receptors (2). However, one group of antipsychotics, dopamine receptor partial agonists (DRPAs), differs in its effects on the dopamine system. Unlike most of the other antipsychotic agents, DRPAs also possess intrinsic dopamine D 2 /D 3 agonist activity and act differently (either as agonists or antagonists) in various parts of the brain (3).
At present, three DRPAs have been approved for clinical use: aripiprazole, brexpiprazole, and cariprazine. Comparing their pharmacodynamics, aripiprazole has the highest intrinsic D 2 activity, and cariprazine has the highest D 3 activity (Table 1) (4,5). High intrinsic D 2 activity can explain activating effects of aripiprazole; high selective affinity for D 3 receptors of cariprazine is effective on positive, negative, and cognitive symptoms. Moreover, hyperstimulation of D 2 or D 3 receptors can cause restlessness, akathisia, agitation, insomnia, nausea, dyspepsia, or rarely compulsive or impulsive behavior (e.g., hypersexuality, compulsive shopping, pathological gambling, and overeating) (4,6). Brexpiprazole with a lower intrinsic D 2 and D 3 has less activating effects and lower risk for akathisia, insomnia, nausea, and dyspepsia.
Pharmacodynamics and pharmacokinetics predict clinical effects and tolerability ( Table 1). Thus, given their variances in pharmacology, it is reasonable to assume that DRPAs differ in their efficacy. There is a paucity of data comparing their antipsychotic effects between each other, the only available (indirect) comparison is based on the number needed to treat (NNT) (4,7). To assess potential differences in the efficacy of DRPAs further, we reexamined data from randomized controlled trials, systematic reviews, and meta-analyses.

METHODS
All publicly available records on PubMed, Cochrane Library, and ClinicalTrials.gov were searched using the key words "aripiprazole, " "brexpiprazole, " or "cariprazine." Included were randomized, double-blind trials with neuropsychiatric patients that examined clinical efficacy. Additional entries were obtained through appropriate references; retrieved records were checked for duplicity. In addition to the randomized controlled trials (RCTs) as the primary data source, meta-analyses of DRPAs assessing comparative efficacy (between DRPAs, DRPAs vs. placebo or standard treatment) or generalizing efficacy data were included, where available. If there was more than one metaanalysis examining the same subject, the most inclusive and/or methodologically sound one was used. The results were reviewed by the authors narratively according to the conditions in which the drugs were tested.

Clinical Efficacy
A total of 143 randomized, double-blind, placebo-or activecomparator controlled trials of DRPAs were identified as of August 31, 2021. The therapeutic efficacy of aripiprazole, brexpiprazole, and cariprazine was tested in 68 RCTs with schizophrenia ( Table 2), 26 RCTs with bipolar disorder, 19 RCTs with major depression ( Table 3), and 30 RCTs in other neuropsychiatric disorders ( Table 4).

Schizophrenia-Acute Treatment
Aripiprazole was found to be superior to placebo in numerous short-term studies of adult patients with acute schizophrenia. A recent comprehensive meta-analysis comparing the antipsychotic efficacy of 32 oral drugs analyzed a total of 27 placebo-or active-comparator-controlled RCTs with aripiprazole (8). The oral formulation of aripiprazole was significantly more efficacious than placebo in the overall change of symptoms (n = Moreover, the antipsychotic efficacy of aripiprazole was compared with risperidone in four RCTs (in two of them, it was used to control for study sensitivity). It was compared with olanzapine in four RCTs, with haloperidol in three placebocontrolled RCTs, and with ziprasidone in one RCT (8). In the pairwise comparisons, aripiprazole was as effective as all active comparators ( Table 2).
Aripiprazole was found to be more effective than placebo in the treatment of children and adolescents with schizophrenia (9). The results of a 6-week RCT showed that 10 or 30 mg/day of aripiprazole in patients 13-17 years old improved schizophrenia symptoms, as measured by the PANSS, Clinical Global Improvement (CGI), and Children's Global Assessment Scale. The difference from placebo in the total PANSS score at study end was significant for both doses, 10 mg (p = 0.05) and 30 mg (p = 0.007).
The antipsychotic efficacy of cariprazine has been proven by the results of four, 6-week RCTs in acute schizophrenia (8).

Schizophrenia-Relapse Prevention
For maintenance treatment and prevention of schizophrenia relapse, oral aripiprazole outperformed the placebo or haloperidol in three long-term trials. In a 26-week study, 310 patients were randomized to aripiprazole 15 mg/day or placebo (10). The time to relapse was significantly longer for aripiprazole than for placebo (p < 0.001), and more patients relapsed on placebo (57%) than on aripiprazole (34%). The relative risk of relapse for the aripiprazole group was 0.59 (95% CI 0.35, 0.71; p < 0.001), the risk was reduced by 41%. Additionally, 30 mg of aripiprazole daily was as effective as 10 mg/day of haloperidol in two, 1-year RCTs with similar protocols, and the total study sample consisted of 1,294 patients (11). Based on a 30% improvement in the Positive and Negative Syndrome Scale (PANSS) total score maintained for at least 28 days, aripiprazole produced a significantly higher response rate than haloperidol (52 vs. 44%; p < 0.003). Time to discontinuation for any reason was significantly greater with aripiprazole than with haloperidol (p = 0.0001), more relapses or treatment failures were reported for haloperidol (21%) than aripiprazole (17%). Compared with haloperidol, aripiprazole reduced the risk of relapse by 19% (hazard ratio HR = 0.81, 95% CI 0.57, 1.14).
The long-term efficacy of brexpiprazole in maintenance treatment of schizophrenia was evaluated in a year-long, doubleblind trial (12). Patients with acute psychotic symptoms were switched to open-label treatment with brexpiprazole 1-4 mg/day over a period of 1-4 weeks. Patients completing the conversion phase entered a 12-to 36-week stabilization phase. In this phase, patients were titrated to a dose of brexpiprazole (1-4 mg/d). Those who remained stable (n = 202) were then randomized to continuation treatment with either their stabilization dose of brexpiprazole or placebo. Compared with placebo, brexpiprazole significantly delayed the time to relapse (p < 0.0001) and reduced relapse risk by 71% (HR = 0.29, 95% CI 0.16, 0.55). The proportion of patients meeting the criteria for impending relapse was 13.5% with brexpiprazole and 38.5% with placebo (p < 0.0001), the relative risk of relapse for the brexpiprazole group was 0.35.
A 97-week, placebo-controlled, multicenter study assessed efficacy of cariprazine in the long-term maintenance treatment of schizophrenia (13). In the first open phase, during an 8week run-in period, the patients were given a flexible dose of cariprazine 3-9 mg/daily and then kept on a fixed dose over
The specific effect of cariprazine on negative symptoms of schizophrenia was investigated in a separate, actively controlled RCT (15). A total of 461 patients with predominant negative symptoms and minimum positive symptoms were randomized to 26 weeks of treatment with either cariprazine (4.5 mg/day) or risperidone (4 mg/day). Cariprazine produced a greater reduction of negative symptoms than risperidone, and the difference was consistently significant from week 14 to the end of the study. The cariprazine-induced change in the PANSS factor score for negative symptoms was −8.90 vs. −7.44 points in the risperidone group; the least squares mean difference (LSMD) was −1.46 (95% CI −2.39, −0.53; p = 0.0022), effect size (ES) at 0.31. Cariprazine also outperformed risperidone in the secondary efficacy measure, the Personal and Social Performance Scale, the change of the total score was 14.30 for cariprazine vs. 9.66 for risperidone; (LSMD = 4.63, 95% CI 2.71, 6.56; p < 0.0001; ES = 0.48).

Bipolar Disorder-Manic Episode
Aripiprazole monotherapy in the management of the acute manic phase of bipolar disorder was tested in seven RCTs, four 3-week and three 12-week studies, with a total of 2,303 patients (16). In all but one trial, aripiprazole was compared with placebo, in two it was compared with haloperidol, and in one it was compared with lithium. Across all studies, aripiprazole achieved significantly higher response and remission rates than placebo.  (16). In addition to monotherapy, aripiprazole at 15 and 30 mg/day (n = 1,101) was found to be effective for acute mania as an addon therapy to lithium or valproate compared with placebo or haloperidol (17). Aripiprazole demonstrated similar efficacy for improving manic or mixed episodes, psychotic or non-psychotic manic episodes, or rapid cycling. Two 3-week, placebo-controlled RCTs with brexpiprazole for acute mania were negative (18). In the total sample of 654 patients, brexpiprazole (flexible dosing of 2-4 mg/day, titrated to a maximum of 4 mg/day) failed to separate from the placebo in the reduction of the YMRS score. Response or remission rates were not reported. A gradual improvement of manic symptoms was observed only in a 26-week, open-label extension in the subjects who completed acute studies (n = 381): the mean decrease of the YMRS total score was −14.0 (SD 8.9).

Bipolar Disorder-Depressive Episode
Neither aripiprazole monotherapy (5-30 mg/day) nor adjunctive therapy was found to be effective in the treatment of depressive episode of bipolar disorder. Although aripiprazole in two 8-week RCTs (n = 749) reduced the severity of depressive symptoms, its efficacy did not separate it from placebo (21). No double-blind controlled studies of brexpiprazole in bipolar depression have been reported.
Cariprazine monotherapy dosed within the range of 0.25 to 3 mg daily was tested in two 6-week and two 8-week, placebocontrolled studies with 1,799 patients (20). The primary results of one 8-week study were negative. In all others, cariprazine at 1.5 or 3.0 mg/day improved symptoms of acute bipolar depression. The effect size of cariprazine at 1.5 mg in the reduction of the Montgomery-Asberg Depression Rating Scale (MADRS) scores was −0.26 (95% CI −0.49, −0.02; p = 0.040), and the ES for 3 mg cariprazine was −0.21 (95% CI −0.41, −0.01; p = 0.045).

Bipolar Disorder-Maintenance Therapy
No DRPA has established efficacy in the prophylaxis of both symptom domains of bipolar disorder. Only aripiprazole was found to be effective in preventing relapse to mania in both monotherapy and in combination with mood stabilizers. Moreover, there is an ongoing trial with cariprazine in the relapse prevention of bipolar disorder, but the results are not available yet (22). No study of brexpiprazole in the maintenance treatment is registered.
In a placebo-controlled trial of 161 patients, aripiprazole doses of 15 and 30 mg daily were effective in delaying the time to manic relapse after 26 and 100 weeks but not in preventing relapse to depression (23,24). At week 26, aripiprazole-treated patients had significantly fewer relapses (25%) than patients on placebo (43%; p = 0.013).
A 52-week study of addon aripiprazole 10-30 mg/day in combination with lithium or valproate demonstrated significantly better efficacy over placebo in the prevention of relapses in patients with mania (p < 0.01) but not in subjects with mixed episodes (25). In a randomized sample of 337 patients, there was a significantly greater reduction in the YMRS total score from baseline with aripiprazole in both manic (treatment difference = −3.32, p < 0.01) and mixed episode populations (treatment difference = −2.56, p = 0.02).

Bipolar Disorder-Children and Adolescents
Aripiprazole was tested in several RCTs in children and adolescents with acute bipolar mania and in maintenance therapy. In a 4-week study with 296 patients 10-17 years old, aripiprazole doses of 10 or 30 mg daily reduced the symptoms of mania significantly more than placebo (26). The response (≥50% reduction in the YMRS total score) was achieved in 44.8, 63.6, and 26.1% of subjects in the aripiprazole 10 mg, aripiprazole 30 mg, and placebo groups, respectively (p < 0.01 for both doses vs. placebo). The acute phase was followed by a 26-week blinded maintenance phase with 210 study subjects (27). The overall time to all-cause discontinuation was longer for 10 mg/day aripiprazole (15.6 weeks) and 30 mg/day aripiprazole (9.5 weeks) than for placebo (5.3 weeks; both p < 0.05 versus placebo). The two aripiprazole doses were significantly superior to placebo in response rates, as well as on all other measures.
Aripiprazole also significantly delayed the time to a new episode (hypomania, mania, mixed state, or continued cycling) in a 72-week, placebo-controlled study of maintenance treatment with 96 bipolar outpatients aged 4-9 years (28). There was a high attrition rate over the first four study weeks: 50% in the aripiprazole group and 90% in the placebo group.
More recently, a placebo-controlled trial investigated the efficacy of aripiprazole (mean dose 7.1 ± 3.7 mg daily) in a study sample of 59 symptomatic patients aged 5-17 years diagnosed with cyclothymia or bipolar disorder not otherwise specified, with high genetic risk for bipolar disorder (30). At week 12, the subjects responded more to aripiprazole than to placebo (reduction of the YMRS total score: p < 0.005).

Depressive Disorder-Adjunctive Treatment
The clinical efficacy of addon aripiprazole in the treatment of unipolar depression with insufficient response to antidepressant therapy was established in three, 6-week RCTs with identical designs (31). Patients who failed to improve during the initial 8 weeks of open-label treatment with antidepressants were randomly assigned to adjunctive aripiprazole (2-20 mg/day, based on tolerability) or placebo. The total study sample comprised 746 patients, and in patients with minimal response to previous antidepressant therapy, adjuvant aripiprazole yielded greater improvement in the MADRS total score than placebo (p < 0.0001), as well as in response rates (36 vs. 19%; p < 0.0001; NNT = 6) and remission rates (24% vs. 12%; p < 0.0001; NNT = 8).
Two small trials (NCT01670279: n = 18 and NCT01837797: n = 15) evaluated the safety and tolerability of brexpiprazole in elderly patients above 65 years and 70-85 years, respectively (22). Efficacy assessment was planned only for the NCT01837797 study. There were 129 enrolled patients, and only 15 patients were randomized to Period 2 (double-blind addon treatment with brexpiprazole at 1 mg, 3 mg, or placebo) before the study was terminated. Due to the limited number of patients, no efficacy data were collected. Unpublished results of a completed 4-week (plus 2-week follow-up) study of brexpiprazole augmentation (up to 3 mg/day) with intranasal ketamine (40 mg) in 51 depressive patients (NCT03149991) were negative (22).
Published were findings of three 8-week, double-blind trials examining the efficacy of cariprazine as an addon treatment of depression with insufficient response to antidepressants. The first 8-week study with 819 patients who did not respond to a minimum of 6 weeks of antidepressant therapy brought positive results (33). Significant improvement in the MADRS total score vs. placebo was observed for cariprazine doses of 2-4.5 mg/day from week 2 (p = 0.011; NNT for response at the endpoint was 9) but not for doses of 1-2 mg/day. The second study with 530 randomized patients failed to demonstrate significant improvement with cariprazine 1.5-4.5 mg daily vs. placebo (34). Similarly, negative results were found in a study with 231 patients that used two cariprazine dosing schedules, 1-2 mg/day or 2-4.5 mg/day (35). Two additional 6-week placebocontrolled RCTs with cariprazine as an adjunctive treatment (1.5-3 mg) to antidepressant treatment in major depression have been completed, but the results are not yet available (22).

Other Neuropsychiatric Disorders
The oral formulation of aripiprazole was investigated in three placebo-controlled RCTs in Alzheimer's disease (36). In the management of psychosis, only one of three 10-week studies met the primary efficacy criteria. In a 10-week, placebo-controlled study with 208 outpatients, the mean age was 81.5 years, and aripiprazole (mean end dose of 10.0 mg/day) yielded greater improvement than placebo only in the Brief Psychiatric Rating Scale (BPRS) psychosis (p < 0.03) and core (p < 0.04) subscales but not in the primary outcome measure, the caregiver assessment Neuropsychiatric Inventory (NPI) psychosis subscale (37). The second study with 256 inpatients used flexible dosing of aripiprazole (2 to 15 mg/day) with a mean aripiprazole dose at the endpoint of 8.6 mg/day (38). There was no significant difference between aripiprazole and placebo in the NPI psychosis subscale, only in several secondary measures, suggesting efficacy on agitation, anxiety, and depression. In the third study, 487 institutionalized nursing home patients were randomized to placebo or fixed doses of aripiprazole at 2, 5, or 10 mg/day (39). Aripiprazole at 10 mg/day produced a statistically significant improvement vs. placebo on the NPI-Nursing Home (NPI-NH) Psychosis subscale score (−6.87 ± 8.6 vs. The clinical efficacy and safety of brexpiprazole in the management of agitation associated with Alzheimer's disease was tested in two placebo-controlled RCTs (40). Both studies were 12-week trials. Study 1 (n = 433) used a fixed dose of 2 mg of brexpiprazole daily, and Study 2 (n = 270) used a flexible dosing schedule of 0.5-2.0 mg/day. The results showed that agitation, measured by the reduction of CMAI score, was reduced by a dose of 2 mg, but not by lower doses. The dose of 2 mg in Study 1 significantly outperformed placebo (adjusted mean difference −3.77, 95% CI −7.38, −0.17; p = 0.040), and post hoc analysis of Study 2 also found better efficacy of the maximum dose of 2 mg (−5.06, 95% CI −8.99, −1.13; p = 0.012).
Two small double-blind, placebo-controlled studies examined aripiprazole addon to SSRIs in the treatment of obsessivecompulsive disorder (OCD). In the first trial, 40 patients were randomized to 16 weeks of administration of aripiprazole 15 mg/day or placebo (41). Among the 30 completers, adjunctive aripiprazole treatment achieved significantly greater improvement on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score and subscores (obsessions, p = 0.007; compulsions, p = 0.001; total score, p < 0.0001). The second study was a 12-week trial with 39 patients, 32 of whom were evaluable (42). The results were positive, and a fixed aripiprazole dose of 10 mg/daily reduced the Y-BOCS total score significantly more than placebo (p < 0.0001). Compared with other antipsychotics in treatment-resistant OCD, addon aripiprazole was less effective than risperidone in a singleblind study (43) and quetiapine in a double-blind RCT (44). However, in a network meta-analysis of 20 RCTs with 790 patients comparing the efficacy and tolerability of antipsychotics in treatment-resistant OCD, aripiprazole did not differ from risperidone, haloperidol, olanzapine, quetiapine, or paliperidone (45). After excluding studies with an overall high risk of bias, only aripiprazole was significantly superior to placebo (mean difference: −7.32, 95% CI −12.99, −1.66).
Several controlled trials tested adjuvant aripiprazole in substance use disorders and in patients with comorbid substance use and schizophrenia or depression (49,50). The findings from studies on cocaine or amphetamine/methamphetamine dependence remain inconclusive.
In addition to human laboratory and neuroimaging studies, aripiprazole monotherapy was investigated in several open and controlled clinical trials of the treatment of alcohol dependence (51). In a 12-week, placebo-controlled study with 295 patients, aripiprazole failed to outperform placebo on the primary outcome measure, percentage of days abstinent, and percentage of subjects without a heavy drinking day and the time to first drinking day (52). Aripiprazole (5-15 mg/day) was as effective as naltrexone (50 mg) in a 16-week study of 75 patients in the number of alcohol-free subjects, the number of subjects who relapsed, the mean number of abstinent days, and heavy drinking days (53). Patients treated with aripiprazole remained abstinent for a longer time than those treated with naltrexone, but naltrexone treatment resulted in a greater reduction in craving scores.

Other Drug Formulations
Aripiprazole is the only DRPA available in various drug formulations. In addition to oral formulation of tablets, orally disintegrating tablets, oral solution, intramuscular (acute) injections, or long-acting (depot) injections (LAI). In 2017, the US Food and Drug Administration (FDA) approved aripiprazole tablet with ingestible sensor, using a digital ingestion system to monitor whether the medication was taken. Long-acting injectable brexpiprazole is currently under clinical investigation; no efficacy data are accessible (22).
Aripiprazole LAI was also tested for schizophrenia relapse prevention. ALAI monohydrate at a dose of 400 mg per 4 weeks was superior to placebo in a 1-year study with 403 patients (56). The trial was terminated prematurely because efficacy was already demonstrated by the preplanned interim analysis. The time to impending relapse was significantly delayed with ALAI treatment compared with placebo in both the interim analysis and the final analysis (p < 0.0001). Additionally, ALAI 400 mg once-monthly showed non-inferiority to oral aripiprazole in two long-term trials. In the first study, 662 patients were randomized to 26 weeks of treatment with ALAI or 10-30 mg/day of oral aripiprazole (57), and the second 1-year study with 455 patients used 6-24 mg/day oral aripiprazole (58).
A randomized, open-label, rater-blinded study compared head-to-head ALAI monohydrate (400 mg once-monthly) with paliperidone palmitate LAI (PP-LAI; 78-234 mg once-monthly) over the course of 28 weeks of treatment (61). The study sample consisted of 295 schizophrenia patients, and the primary outcome measure was the Heinrichs-Carpenter Quality-of-Life Scale (QLS). The results revealed a statistically significant least squares mean difference between the treatments in the change from baseline to week 28 on the QLS total score [4.67 (95% CI 0.32, 9.02), p = 0.036] in favor of ALAI over PP-LAI, suggesting superiority of ALAI on clinician-rated quality of life. Moreover, ALAI was also significantly more efficacious for clinical improvement measured by the change in the CGI-S (p < 0.01).
The primary goal of a naturalistic, 1-year randomized trial was to compare clinical efficacy, substance craving intensity, and quality of life between aripiprazole LAI (400 mg once-monthly) and paliperidone LAI (100 mg once-monthly) in 101 patients with psychosis (schizophrenia spectrum or bipolar disorder) and comorbid substance use (62). The results showed that both drugs yielded significant improvements, with a comparable effect in the reduction of psychopathology, but aripiprazole was superior in the improvement of quality of life and craving reduction.
A short-acting intramuscular injectable formulation of aripiprazole was effective at reducing acute agitation associated with psychosis in two placebo-controlled studies with an analogous design (63,64). Aripiprazole (1-15 mg i.m.), haloperidol, or placebo were administered to a total of 805 acutely psychotic patients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder. The doses of aripiprazole, 5.25 or 9.75 mg, significantly outperformed placebo and were as effective as an active comparator of a haloperidol intramuscular injection (6.5-7.5 mg/day). Compared with placebo, aripiprazole produced a 1.5-to 2-fold greater reduction in mean PANSS-Excited Component scores (PANSS-EC) 2 h after the first dose (primary endpoint).
An intramuscular injectable formulation of aripiprazole significantly reduced acute agitation associated with manic episode in a single, placebo-controlled trial (65). A study sample of 301 acutely agitated bipolar patients was randomized to 9.75 or 15 mg of aripiprazole injection, lorazepam 2 mg i.m., or placebo. Aripiprazole at doses of 5 mg and higher was superior to placebo and as effective as lorazepam. Improvements in the PANSS-EC scores at 2 h were significantly greater with i.m. aripiprazole (9.75 mg, −8.7; 15 mg, −8.7) and i.m. lorazepam (−9.6) vs. i.m. placebo (−5.8; p ≤ 0.001).
Aripiprazole i.m. injection showed efficacy in the reduction of acute agitation in Alzheimer's, vascular, or mixed dementia in a trial with a primary outcome of tolerability and safety (66). In a 24-h study of 129 inpatients, doses of 10 or 15 mg (but not 5 mg) were superior to placebo in the improvement of PANSS-PEC at 30 min and maintained their superiority throughout the 24-h study.

Comparative Efficacy
None of the double-blind randomized studies in various indications compared directly, head-to-head, efficacy between the reviewed dopamine receptor partial agonists. Three acute schizophrenia trials, two double-blind and one open-label, used aripiprazole as an indirect comparator of the tested DRPAs to control for study sensitivity (22,67,68).
The objective of a placebo-controlled, 6-week Phase II RCT (NCT00905307) was to establish the optimal dose of brexpiprazole in acute schizophrenia based on efficacy, safety, and tolerability (22). The results have not been published yet. In a failed study with a sample of 459 patients, active treatment  (7), bipolar depression (71,72), and major depression (70). arms (brexpiprazole at doses of 0.25 mg, 1 ± 0.5 mg, 2.5 ± 0.5 mg, 5 ± 0.5 mg, or aripiprazole 15 ± 5 mg daily) did not differ significantly from placebo in any of the efficacy measures.
Aripiprazole as a positive control to confirm assay sensitivity was also included in an open-label randomized study of brexpiprazole in acute schizophrenia (68). The study aim was to explore changes in efficacy, cognitive functioning, and safety over the course of 6 weeks of treatment with flexibly dosed brexpiprazole (target dose 3 mg/day) or aripiprazole (target dose 15 mg/day) monotherapy. A total of 97 schizophrenia patients were randomly (2:1) assigned to a 6-week open treatment. Improvement observed in the PANSS total score was comparable in both treatment arms: the least squares mean improvement observed at week 6 was −22.9 points for brexpiprazole (p < 0.0001 vs. baseline) and −19.4 points for aripiprazole (p < 0.0001 vs. baseline).
In clinical practice, the number needed to treat (NNT) represents a useful tool for indirect comparison of therapeutic effects measured by categorical outcomes. NNT indicates how many patients need to be treated with a new treatment to see an additional improvement over a comparator, with lower numbers, single digits, indicating clinically relevant differences. Citrome comprehensively analyzed NNT and the number needed to harm for adverse events and likelihood to be helped or harmed of the DRPAs vs. placebo in registration studies (7,69). The comparative efficacy of DRPAs in adjuvant treatment of major depression measured by NNT can be extracted from a recent meta-analysis (70). NNT for treatment response from pivotal trials in schizophrenia, bipolar disorder, and major depression are summarized in Table 5.
Likewise, no statistically significant differences between the DRPAs in treatment responses can be detected for acute mania or adjunctive treatment of major depression. The NNT for response in bipolar mania (≥50% decrease in the YMRS total score) was 5 (95% CI 4, 18) for cariprazine 3-6 mg/day and 7 (95% CI 5, 11) for aripiprazole 15-30 mg/day (7). In bipolar depression, only cariprazine demonstrated a positive effect, studies with aripiprazole produced negative results, and no studies with brexpiprazole have been reported. The NNT for cariprazine in bipolar depression was 10 (95% CI 7, 12) for response and 11 (95% CI 8, 22) for remission (73). Non-significant NNT (>45) for aripiprazole confirms the superiority of cariprazine for the treatment of bipolar depression (71).
Other options for comparing efficacy provided metaanalyses. A systematic review and network meta-analysis that included 3,925 patients indirectly compared aripiprazole with brexpiprazole in acute schizophrenia therapy (74). The results confirmed that the response rates of both antipsychotics were significantly superior to placebo: aripiprazole RR = 0.84 (95% CI 0.78, 0.92) and brexpiprazole RR = 0.84 (95% CI 0.77, 0.92). There was no statistically significant difference between the drugs in their efficacy: brexpiprazole vs. aripiprazole RR = 1.0 (95% CI 0.88, 1.12).
A large network meta-analysis of 32 oral antipsychotics enabled us to compare the acute antipsychotic efficacy of DRPAs with that of other antipsychotic agents and placebo (8). All three DRPAs were more effective than placebo in the overall change in psychotic symptoms. In a pairwise comparison, aripiprazole vs. For the treatment of acute mania, a network meta-analysis confirmed the superior efficacy of aripiprazole and cariprazine over placebo: aripiprazole SMD = 0.37 (95% CI 0.2, 0.55) and In a network meta-analysis of the efficacy and tolerability of second-generation antipsychotic monotherapy in acute bipolar depression, the only DRPA more efficacious than placebo was cariprazine; aripiprazole was not separated from placebo (72). The mean change in the MADRS total score for cariprazine was −2.29 (95% CI −3.47, −1.09), and the odds ratio for response (≥50% improvement in the MADRS) was 1.47 (95% CI 1.17, 1.82). However, the difference in response between cariprazine and aripiprazole failed to reach statistical significance on both outcome measures, change in the MADRS score (SMD = −1.21, 95% CI −3.70, −1.29), and the response rate (OR = 1.35, 95% CI 0.90, 1.95).

Tolerability
DRPAs are generally well tolerated with a favorable safety profile ( Table 6) (4,76). The highest risk of akathisia, dose-dependent, is reported in cariprazine, and the lowest incidence is reported in brexpiprazole. High doses of cariprazine can also induce extrapyramidal symptoms. Brexpiprazole is associated with a medium risk of weight gain. Aripiprazole treatment can cause nausea, less frequent sedation, or pathological gambling or compulsive behavior. A recent review of EudraVigilance data found a higher reporting odds ratio of impulse control symptoms for aripiprazole than for brexpiprazole or cariprazine (77). All DRPAs have a low risk of metabolic and cardiovascular side effects and are considered as prolactin-sparing drugs.
The relationship between efficacy and safety can be assessed indirectly with the measure of likelihood to be helped or harmed (LLH) (78). LLH values of >1.0 signify that benefit (response) is more likely than harm (adverse event). LLH values of ≥10 mean that the response is at least 10 times more likely to occur than the evaluated side effect. In schizophrenia treatment, LLH ≥ 10

DISCUSSION
In the absence of direct head-to-head studies between DRPAs, their comparative efficacy can only be estimated from a synthesis of available preclinical and clinical data (79). The reviewed results from controlled trials and meta-analyses clearly indicate that DRPAs do not represent a fully homogeneous group and possess different therapeutic benefits. This finding only corroborates the fact that the clinical effects of pharmacological agents are directly linked to their pharmacological profiles (4). Our review did not reveal any significant differences between DRPAs in their antipsychotic efficacy, treatment of acute schizophrenia, or relapse prevention. For acute mania, aripiprazole doses above 15 mg/day and cariprazine doses greater than 3 mg/day are clinically effective. Data analysis suggested that cariprazine in the treatment of manic episode may have a particular effect on irritability ( Table 7). The lack of antimanic efficacy of brexpiprazole in two RCTs can be attributed to the high placebo response, slow titration schedule, or regional differences (significant separation from placebo was observed in the EU but not the US study sites). Thus, more studies are needed (18).
In the treatment of bipolar depression, only cariprazine (1.5-3 mg/day) yielded positive results, aripiprazole studies were negative, and no data for brexpiprazole were available. Aripiprazole monotherapy or adjuvant treatment is effective as maintenance treatment of bipolar disorder, only in preventing relapse to mania. The results of a cariprazine trial in the relapse prevention of bipolar disorder are not available yet; no studies have examined the prophylactic efficacy of brexpiprazole.
Aripiprazole (5-15 mg/day) and brexpiprazole (≥2 mg/day) were found to be effective in augmenting treatment-resistant major depression. Post hoc analysis suggested that adjuvant brexpiprazole in depressive disorder produces more anxiolytic and sedative effects. The potential therapeutic benefit of addon cariprazine in unipolar depression reported in a meta-analysis (with equivocal results from individual trials) needs to be further corroborated (70).
Additionally, published data suggest that brexpiprazole is expected to have better efficacy than aripiprazole on cognitive deficit in schizophrenia; cariprazine may specifically improve negative symptoms of schizophrenia. Enhancement of higher cerebral functions by partial dopamine agonism can be explained by the increased dopaminergic transmission in the prefrontal cortex. Analogously, the reduction of negative symptoms by lower doses (100-200 mg/day) of the D 2 /D 3 receptor antagonist amisulpride is ascribed to the fact that at lower concentrations, presynaptic actions prevail and ensure that dopamine is more released at the synapse (80). Efficacy of amisulpride and cariprazine for predominant negative symptoms was also confirmed in a meta-analysis (81).
The first approved DRPA was aripiprazole (launched in the United States in 2002), and it has been used for the longest time period with extensive clinical experience available. Unlike brexpiprazole or cariprazine, aripiprazole was also tested in numerous other indications and special populations: children and adolescents, dementia patients, OCD patients, patients with tic disorders, patients with autism spectrum disorder, clozapine augmentation, and patients with substance use disorders. There are currently several ongoing trials with brexpiprazole and cariprazine in the treatment of other psychiatric conditions (e.g., attention deficit hyperactivity disorder, generalized anxiety disorder, post-traumatic stress disorder, borderline personality disorder, autism spectrum disorder, Alzheimer's dementia, alcohol use, etc.) and more studies in different indications and populations can be expected. Besides long-term availability, more data are available for aripiprazole due to the studies with various drug formulations. Thus, a reliable comparison between DRPAs can be made only for their oral formulas in few indications: schizophrenia, bipolar disorder, and major depression.
It should be noted that the evidence from clinical trials is not fully reflected in approved indications listed in the summary of product characteristics. Moreover, US and EU regulations differ. The European Medical Agency approved all three DRPAs for the treatment of schizophrenia in adults, aripiprazole for schizophrenia in adolescents 15 years of age and older, treatment of bipolar disorder, manic and mixed episodes (adults and adolescents above 13 years), monotherapy or adjuvant treatment in the maintenance treatment of bipolar disorder, and prevention of relapse to mania. The FDA additionally approved aripiprazole as an adjunctive therapy of major depressive disorder in adults, treatment of children and adolescents with acute mania, either as monotherapy or addon therapy to lithium or valproate, treatment of Tourette syndrome in children, irritability associated with autism spectrum disorder, brexpiprazole as an adjunctive therapy of major depression, and cariprazine for acute treatment of adults with manic, mixed, and depressive episodes of bipolar disorder.
Our review is the first comprehensive comparison of the clinical efficacy of partial dopamine agonists across various psychiatric disorders. All available studies, reviews, and metaanalyses, including unpublished records, were analyzed. The findings, summarized in Table 7, can provide useful guidance for clinicians in psychiatric practice. The results were reviewed qualitatively; heterogeneity of the data and the lack of studies in some indications did not allow more detailed statistics beyond NNT. Moreover, due to the primary focus on efficacy and space limitations, we provide only a brief overview and a general comparison of side effects, without specific details for different conditions or patient populations.
While our review focused solely on double-blind, controlled studies, we should be aware of their shortcomings, especially the limited generalizability of the results. Subject selection for RCTs, especially placebo-controlled RCTs, is biased and not representative of the general psychiatric population (82). To fully assess the efficacy and safety of any treatment, real-world data are needed. Finally, efficacy is just one of the factors in the selection of treatment. Although we exclusively examined differences in the therapeutic effects, choosing a drug for a specific patient should always be individualized, balancing risks vs. benefits, considering not only efficacy but also drug tolerability, safety profile, and preferences of the patients.

CONCLUSIONS
The clinical efficacy of aripiprazole, brexpiprazole, and cariprazine in the treatment of various psychiatric disorders has been confirmed in numerous RCTs. Although there are no direct head-to-head comparisons between them, indirect appraisals indicate that there are clinically meaningful differences in their effects that can be attributed to their specific pharmacological profiles. More RCTs with brexpiprazole and cariprazine for various indications are needed, as well as head-to-head studies examining the variances of DRPAs in their efficacy and safety.

AUTHOR CONTRIBUTIONS
PM, JM, and MK contributed equally to the study design, data collection, and interpretation of the findings. PM drafted the original manuscript. JM and MK reviewed and edited the paper. All authors contributed to the article and approved the submitted version.