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 = 1,926 patients; standardized mean difference (SMD) = −0.41, 95% CI −0.50, −0.32), positive symptoms (n = 1,451; SMD = −0.38, 95% CI −0.48, −0.28), negative symptoms (n = 1,353; SMD = −0.33, 95% CI −0.41, −0.24), and depressive symptoms (n = 150; SMD = −0.40, 95% CI −0.69, −0.10), but not in social functioning (n = 50; SMD = −0.23, 95% CI −0.55, 0.09).

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 placebo-controlled 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 efficacy of brexpiprazole 2 and 4 mg in the treatment of acute schizophrenia was established in six RCTs (8). Brexpiprazole was more effective than placebo in overall symptom reduction (n = 1.180; SMD = −0.26, 95% CI −0.39, −0.12), improvement of positive symptoms (n = 1,180; SMD = −0.17, 95% CI −0.31, −0.04), negative symptoms (n = 1,180; SMD = −0.25, 95% CI −0.36, −0.14), depressive symptoms (n = 1,090; SMD = −0.16, 95% CI −0.29, −0.03), and social functioning (n = 918; SMD = −0.25, 95% CI −0.38, −0.12).

The antipsychotic efficacy of cariprazine has been proven by the results of four, 6-week RCTs in acute schizophrenia (8). Compared with placebo, cariprazine improved significantly more overall symptoms (n = 999; SMD = −0.34, 95% CI −0.49, −0.20), positive symptoms (n = 999; SMD = −0.30, 95% CI −0.45, −0.16), negative symptoms (n = 999; SMD = −0.34, 95% CI −0.44, −0.20), and depressive symptoms (n = 305, SMD = −0.36, 95% CI −0.63, −0.09). No data on social functioning of cariprazine were obtainable from acute trials.

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, double-blind 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 8-week 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 course of a 12-week stabilization period. The patients (n = 200) were subsequently randomized to a blinded administration of cariprazine (3, 6, or 9 mg/day) or placebo. Double-blind phase lasted from 26 to 72 weeks. The results demonstrated that maintenance treatment with cariprazine was superior to placebo in terms of time to relapse (p < 0.001), and the risk of relapse was reduced by 55% (HR = 0.45, 95% CI 0.28, 0.73). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients; the relative risk of relapse for the cariprazine group was 0.52.

Aripiprazole demonstrated efficacy in augmenting clozapine in treatment-resistant schizophrenia in short- and long-term treatments (14). In a systematic review and meta-analysis of seven placebo-controlled trials (duration from 8 to 24 weeks) with 486 clozapine-refractory patients, addon aripiprazole produced improvement in the total psychotic symptoms (SMD = −0.57, 95% CI −1.02, −0.13) and in negative symptoms in five RCTs (n = 328; SMD = −0.33, 95% CI −0.55, −0.11). However, the reduction of positive symptoms was nonsignificant (n = 328; SMD = −0.15, 95% CI −0.60, 0.30).

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).

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. Response was defined as ≥50% improvement in the Young Mania Rating Scale (YMRS) total score, remission as the YMRS total score ≤12. At week 3, the average response rate was 47.70% for aripiprazole, 45.99% for the comparator agents, and 31.40% for placebo. At week 12, the response rate was 59.12% for aripiprazole and 50.63% for the controls. A meta-analysis of the effect sizes (aripiprazole vs. placebo) suggested a pooled d-value equal to 0.34 (95% CI 0.24, 0.44) for YMRS (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).

A summary analysis of three placebo-controlled studies with cariprazine in the treatment of acute manic or mixed episode included 1,037 patients (19). Trial designs were similar; after a week-long washout period, patients received a 3-week, double-blind treatment. Two studies used a flexible dosing schedule of cariprazine, 3–12 mg daily, and the third included two active groups of 3–6 mg/daily and 6–12 mg daily. The results at week 3, measured by the YMRS score reduction, demonstrated significant efficacy of cariprazine in the management of acute mania compared with placebo in response (57 vs. 36%; NNT = 5) and remission (46 vs. 30%; NNT = 7) rates. Cariprazine was superior to placebo in the effect size for both response rate (ES = 2.31, 95% CI 1.35, 3.95; p = 0.021) and remission rate (ES = 2.05, 95% CI 1.61, 2.61; p = 0.006) (20). The risk difference (RD) of response rates was 0.204 (95% 0.090, 0.317; p = 0.0163; NNT = 5), the RD of remission rates was 0.165 (95% 0.125, 0.206; p = 0.003; NNT = 6).

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, placebo-controlled 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).

Cariprazine at 1.5 mg/day produced non-significant response rates on MADRS (≥50% reduction of the MADRS score) with an ES of 1.53 (95% CI 0.78, 2.99; p = 0.113) and a trend for higher remission rates on MADRS (MADRS score ≤10) with an ES of 1.75 (95% CI 0.96, 3.22; p = 0.057). The RD of response rates on MADRS was 0.10 (95% −0.06, 0.26; p = 0.112; NNT = 10, the RD of remission rates was 0.10 (95% −0.02, 0.23; p = 0.072; NNT = 10). The 3 mg/day of cariprazine yielded a statistically significant ES for response rate according to the MADRS, with an odds ratio (OR) of 1.55 (95% CI 1.11, 2.17; p = 0.030) and a remission rate with an OR of 1.53 (95% CI 1.36, 1.72; p = 0.043). The RD of response rates according to MADRS was 0.10 (95% 0.02, 0.18; p = 0.030; NNT = 10). The RD of remission rates was 0.07 (95% 0.04, 0.11; p = 0.01; NNT = 14) (20).

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).

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.

A small 6-week study with 43 patients aged 8–17 years old who suffered from mania comorbid with ADHD found that aripiprazole (mean dose 13.6 ± 5.4 mg daily) was effective at reducing YMRS score vs. placebo (p = 0.02; ES = 0.80) (29). Aripiprazole also achieved higher rates of response (p = 0.02) and remission (p = 0.01).

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).

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).

A meta-analysis of nine 6- to 24-week RCTs of brexpiprazole for augmentation of antidepressant therapy (total n = 3673) showed that brexpiprazole was more effective than placebo for all outcome measures (32). Brexpiprazole was administered in fixed or flexible doses within a range of 0.5–3 mg/day, and one study used quetiapine XR as an active comparator. Treatment with brexpiprazole resulted in a higher response rate (risk ratio RR = 0.93, 95% CI 0.89, 0.97; NNT = 17), remission rate (RR = 0.95, 95% CI 0.93, 0.98; NNT = 25), and reduction of the MADRS total score (SMD = −0.20, 95% CI −0.29, −0.11). Doses beyond 2 mg/day produced a significantly greater RR than doses ≤2 mg/day (RR 0.96 vs. 0.89).

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 placebo-controlled 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).

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. −5.13 ± 10.0; p = 0.013) at week 10, as well as on the secondary measures [BPRS, CGI, Cohen-Mansfield Agitation Inventory (CMAI)].

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 obsessive–compulsive 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 single-blind 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).

A meta-analysis of 17 RCTs in the treatment of tic disorders and Tourette syndrome in children and adolescents that comprised 1,305 subjects, found aripiprazole to be as effective as other therapeutics, haloperidol, topiramate, risperidone, or tiapride (46). According to a recent network meta-analysis of 60 RCTs with antipsychotics for tic disorders, aripiprazole was superior to placebo (SMD = −4.74, 95% CI −8.67, −1.06) and tiapride (SMD = −4.27, 95% CI −8.01, −0.58) (47).

The efficacy of aripiprazole in the management of behavioral impairments in children and adolescents with autism spectrum disorders was examined in a meta-analysis of three RCTs that included 408 patients (48). The change in psychiatric symptoms and behavioral disturbances measured by the Aberrant Behavior Checklist showed that compared with placebo, aripiprazole significantly reduced scores across various domains: irritability (weighted mean difference, WMD −5.41, 95% CI −7.58, −3.24), hyperactivity/non-compliance (WMD = −7.68, 95% CI −9.92, −5.45), inappropriate speech impairments (WMD = −1.23, 95% CI −2.08, 0.38), and stereotypic behavior (WMD= −2.04, 95% CI−3.33, −0.74), but not lethargy/social withdrawal. The overall pooled response rate of the aripiprazole-treated group was significantly higher than that of the placebo-treated group, with an RR of 2.08 (95% CI 1.24, 3.46), and the NNT was 4 (95% CI 2.8, 5.7).

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.

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).

Both formulations of long-acting injectable aripiprazole (ALAI) once-monthly, ALAI monohydrate and ALAI lauroxil, were effective in two 12-week studies of acute schizophrenia exacerbation (54, 55). In a study sample of 340 patients, ALAI monohydrate 400 mg reduced PANSS total score at week 10 significantly more than placebo (mean difference in the least square (LS) change: −15.1, 95% CI −19.4, −10.8; p < 0.0001) and the CGI-Severity score (CGI-S) (LS −0.8, 95% CI −1.1, −0.6; p < 0.0001) (54). ALAI lauroxil also outperformed placebo in the PANSS total score improvement in a study with 623 patients (55). The difference (LS) in the 441 mg group was −10.9 ± 1.8 (p < 0.001) and in the 882 mg group was −11.9 ± 1.8 (p < 0.001). The proportion of patients who were very much or much improved on the CGI-Improvement (CGI-I) scale was significantly greater with aripiprazole lauroxil 441 and 882 mg treatments vs. placebo (p < 0.001).

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).

ALAI monohydrate 400 mg once-monthly also showed prophylactic efficacy for bipolar disorder (59, 60). In a 1-year study with 266 patients, ALAI significantly delayed the time to recurrence of any mood episode compared with placebo (hazard ratio HR: 0.45, 95% CI, 0.30, 0.68; p < 0.0001) and time to hospitalization (p = 0.0002), with a recurrence rate of 2.3% for the ALAI group vs. 13.5% for placebo (HR = 0.14, 95% CI 0.04, 0.47). ALAI primarily reduced the number of manic episodes (p < 0.0001).

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.