The Effect of Brexpiprazole (OPC-34712) and Aripiprazole in Adult Patients with Acute Schizophrenia: Results from a Randomized, Exploratory Study

192 Original article

The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study Leslie Citromea,AiOtac, Kazuhiro Nagamizuc, Pamela Perryb, Emmanuelle Weillerd and Ross A. Bakerb

The aim of this study was to explore the effects of (9.4%) than aripiprazole (21.2%). Clinically relevant brexpiprazole and aripiprazole on efficacy, cognitive improvements in psychopathology were observed in functioning, and safety in patients with acute schizophrenia. patients with acute schizophrenia treated with Patients who would benefit from hospitalization/continued brexpiprazole or aripiprazole. Brexpiprazole was well hospitalization for acute relapse of schizophrenia were tolerated, with a lower incidence of akathisia than enrolled and randomized (2 : 1) to target doses of open- aripiprazole. Int Clin Psychopharmacol 31:192–201 label brexpiprazole 3 mg/day or aripiprazole 15 mg/day for Copyright © 2016 Wolters Kluwer Health, Inc. All rights 6 weeks. Outcomes included change from baseline to week reserved. 6 in the Positive and Negative Syndrome Scale total score, International Clinical Psychopharmacology 2016, 31:192–201 Barratt Impulsiveness Scale 11-item score, and Cogstate computerized cognitive test battery scores. Patients treated Keywords: akathisia, antipsychotic, aripiprazole, Barratt Impulsiveness Scale 11-item, brexpiprazole, Positive and Negative Syndrome Scale, with brexpiprazole (n = 64) or aripiprazole (n = 33) showed schizophrenia, Specific Levels of Functioning Scale reductions in symptoms of schizophrenia as assessed by aDepartment of Psychiatry and Behavioural Sciences, New York Medical College, Positive and Negative Syndrome Scale total score (− 22.9 Valhalla, New York, bOtsuka Pharmaceutical Development & and − 19.4, respectively). A modest reduction in impulsivity Commercialization Inc., Princeton, New Jersey, USA, cOtsuka Pharmaceutical Co. Ltd, Tokyo, Japan and dH. Lundbeck A/S, Valby, Denmark was observed with brexpiprazole, but not aripiprazole (mean change in the Barratt Impulsiveness Scale 11-item Correspondence to Leslie Citrome, MD, MPH, 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USA total score: − 2.7 and 0.1, respectively). No change in Tel: + 1 845 362 2081; fax: + 1 845 362 8745; Cogstate scores was observed for either treatment. e-mail: [email protected]

Brexpiprazole was well tolerated and the incidence of Received 21 October 2015 Accepted 2 February 2016 akathisia was lower in patients treated with brexpiprazole

Introduction Schizophrenia, in general, remains a complex and Schizophrenia is a chronic and debilitating mental illness difficult-to-treat disorder, despite the number of different (Volavka and Citrome, 2009). Individuals with schizo- antipsychotics commercially available (Volavka and phrenia experience a range of impairments, including Citrome, 2009; Citrome, 2013). Meta-analyses have positive (e.g. hallucinations, delusions), negative (e.g. shown that when comparing groups of patients enrolled social withdrawal, lack of emotion, apathy), and cognitive in clinical trials, first-line second-generation anti- (e.g. memory, attention, problem solving) symptoms psychotics can differ considerably in reported side (Volavka and Citrome, 2009; Levi et al., 2013). Another effects, with smaller differences observed in efficacy (De symptom domain of schizophrenia includes impulsive Hert et al., 2012a; Citrome, 2013; Leucht et al., 2013; behaviors, agitation, and hostility (Citrome, 2007; Ouzir, Citrome and Volavka, 2014). Importantly, efficacy and 2013; Reddy et al., 2014). Schizophrenia not only has a tolerability responses to different antipsychotics can vary profound detrimental effect on the patient’s well-being markedly among individual patients in clinical practice and ability to function in society but also a cost burden of (Citrome, 2013). more than $62 billion per year in the USA (Saha et al., Antipsychotic drugs bind to a variety of dopaminergic, 2005; Wu et al., 2005; Volavka and Citrome, 2009). serotonergic, noradrenergic, histaminic, and muscarinic receptors. Their affinity and intrinsic activity for the D2

Supplemental digital content is available for this article. Direct URL citations receptor varies, with effective blockade being achieved at appear in the printed text and are provided in the HTML and PDF versions of this different dose levels, often resulting in drug concentra- article on the journal's website (www.intclinpsychopharm.com). tions that can lead to the blockade of other receptor This is an open-access article distributed under the terms of the Creative systems, potentially triggering associated side effects Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC- ND), where it is permissible to download and share the work provided it is properly (Correll, 2010). The different receptor-binding profiles of cited. The work cannot be changed in any way or used commercially. current second-generation antipsychotics may contribute

0268-1315 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YIC.0000000000000123 Brexpiprazole and aripiprazole in acute schizophrenia Citrome et al. 193 toward the variability in accompanying side effects with those of aripiprazole (Maeda et al., 2014b). (Correll, 2010), including weight gain, sedation, rest- Furthermore, brexpiprazole showed statistically sig- lessness/agitation, akathisia, QTc prolongation, extra- nificant efficacy and good tolerability compared with pyramidal symptoms (EPSs), and hyperprolactinemia placebo in two recent phase III clinical studies in adult (and associated sexual effects) (Kane et al., 2010; De Hert patients with acute schizophrenia (Correll et al., 2015; et al., 2012b; Leucht et al., 2013). Therefore, selection of Kane et al., 2015). Systematic clinical reviews can be an effective antipsychotic for a patient requires careful found elsewhere (Citrome, 2015a, 2015b). consideration of the agent’s full efficacy and safety profile The aim of this open-label study (ClinicalTrials.gov (Citrome and Volavka, 2014). Antipsychotic treatment NCT02054702) was to explore changes in efficacy, cog- selection requires the careful balancing of activating and nitive functioning, and safety of a 6-week treatment with sedating side effects, as well as minimizing the risk for flexibly-dosed brexpiprazole or aripiprazole monotherapy EPSs, metabolic, and cardiovascular events associated in patients with schizophrenia. Aripiprazole was included with various antipsychotic agents. as a positive control to confirm assay sensitivity in Brexpiprazole (OPC-34712) is a serotonin-dopamine this study. activity modulator (Maeda et al., 2014a). It acts as a partial agonist at the serotonin 5-HT1A and dopamine D2 Patients and methods receptors, and as an antagonist at 5-HT2A and nora- Patients drenaline α1B/2C receptors (Maeda et al., 2014a), with Adult patients (18–65 years old) with a Diagnostic and similar affinity at all 5 receptors. As reward capacity can statistical manual of mental disorders, 4th ed., text revision be diminished by pure D2 full antagonists, partial D2 (DSM-IV-TR) diagnosis of schizophrenia that was con- agonists may preserve reward capacity mediated by D2 firmed by the Mini International Neuropsychiatric receptors and thus contribute toward improved patient Interview for Schizophrenia and Psychotic Disorders functioning and autonomy (Stahl, 2008). Both brexpi- (Sheehan et al., 1998) were recruited to participate. prazole and aripiprazole (available commercially since Patients were eligible if, in the investigator’s opinion, 2002) are second-generation antipsychotics that act as they might potentially benefit from hospitalization or partial agonists at D2 and serotonin 5-HT1A receptors and continued hospitalization with brexpiprazole or aripipra- as antagonists at the 5-HT2A receptor (Shapiro et al., zole monotherapy for the treatment of a current acute 2003; Maeda et al., 2014a). However, aripiprazole has relapse of schizophrenia. Patients had to be experiencing been associated with inducing D2 agonist-mediated an acute exacerbation of psychotic symptoms and marked adverse events (AEs) such as akathisia, insomnia, rest- deterioration of usual function as shown by all of the lessness, agitation, and nausea (Fleischhacker, 2005; following: Positive and Negative Syndrome Scale Otsuka Pharmaceutical Co. Ltd, 2016). (PANSS) (Kay et al., 1987) total score of 80 or more; score of 4 or more at screening on two or more PANSS items of Brexpiprazole has a lower intrinsic activity at the D 2 hallucinatory behavior, unusual thought content, con- receptor than aripiprazole, and as such should induce ceptual disorganization, or suspiciousness; and Clinical fewer D agonist-mediated AEs. In addition, brexpipra- 2 Global Impression-Severity of Illness Scale (CGI-S) score zole has a higher affinity at the 5-HT receptor than 2A 4 or more (moderately ill). Patients were excluded if they aripiprazole and as 5-HT antagonism may reduce D 2A 2 were presenting with a first episode of schizophrenia, had antagonist-induced akathisia (Laoutidis and Luckhaus, been hospitalized for more than 21 days for the current 2014), brexpiprazole may have the potential to be asso- acute episode, had a current DSM-IV-TR Axis 1 diag- ciated with fewer EPS-related events compared with nosis other than schizophrenia, or they showed an aripiprazole. Brexpiprazole also shows higher affinity for improvement of 20% or more in the total PANSS score the 5-HT receptor than aripiprazole, which could have 1A between the screening and the baseline assessments. potential benefits on depressive symptoms common in patients with schizophrenia (Blier and Ward, 2003; Study design Celada et al., 2004; Maeda et al., 2014b). Higher affinity at This was a 6-week, phase IIIb, exploratory, open-label, the α adrenergic receptor for brexpiprazole than aripi- 1 multicenter, flexible-dose study in adult patients carried prazole may also mitigate against EPS-related effects out between 27 February 2014 and 25 July 2014 at 19 (Stahl, 2013), and may also be useful in managing agita- sites across the USA. tion and sleep disturbances. The α1 antagonist prazosin, for example, has been shown to improve agitation asso- The study consisted of a 2–14-day screening phase to ciated with Alzheimer’s disease (Wang et al., 2009) and assess eligibility and to wash out previous antipsychotic hyperarousal/sleep disturbances associated with post- medications and any prohibited concomitant medica- traumatic stress syndrome (De Berardis et al., 2015). tions, a 6-week treatment phase in which patients were Brexpiprazole has shown robust effects on positive randomly assigned 2 : 1 to receive brexpiprazole or ari- symptoms and cognitive impairment in relevant animal piprazole, and a 30-day follow-up phase (Fig. 1). Once models, with superior effects in cognitive tests compared informed consent was obtained, all participants were 194 International Clinical Psychopharmacology 2016, Vol 31 No 4

Fig. 1

Safety Screening 6-week treatment period follow-up

Brexpiprazole 1, 2, 3 (target dose), 4 mg/day (n = 64) Adults who would benefit from Initiate at 1 mg/day, titrate to 3 mg/day end of week 1 hospitalization or continued hospitalization for R acute relapse of schizophrenia Initiate at 10 mg/day, 15 mg/day end of week 1 Aripiprazole 10, 15 (target dose), 20 mg/day (n = 33) 1 or more visits Telephone as needed contact

Duration: 6 weeks 2 to 14 days 30 (+2 days) R = randomized (2:1) Baseline visit (N = 97) End of treatment (day 0) (week 6/ET)

Study design schematic. Patients in the brexpiprazole group initiated dosing at 1 mg/day for 4 days, followed by 2 mg/day for 3 days, and titrated to 3 mg/day (the target dose) at the week 1 visit. From the week 1 visit, the dose could increase/decrease in a step-wise manner (1 mg/day) within the range of 1–4 mg/day on the basis of the investigator’s clinical evaluation of the patient’s efficacy and tolerability. Patients assigned to the aripiprazole group initiated dosing at 10 mg/day for 1 week, followed by 15 mg/day at the week 1 visit. From the week 1 visit, the dose could increase/decrease in a step-wise manner (5 mg/day) within the range of 10–20 mg/day on the basis of the investigator’s clinical evaluation of the patient’s efficacy and tolerability. ET, end of treatment.

hospitalized up to at least the week 2 study visit after the Clinical Practice Guidelines, and applicable local laws initiation of active treatment. Eligible patients received and regulatory requirements. flexible dosages of open-label brexpiprazole (1–4 mg/ day) or aripiprazole (10–20 mg/day) starting at 1 mg/day Assessments and titrating to a target dosage of 3 mg/day at the end of The efficacy outcomes included changes from baseline to week 1 for brexpiprazole, and starting at 10 mg/day and week 6 in PANSS total score, CGI-S score, Specific titrating to a target dosage of 15 mg/day at the end of Levels of Functioning Scale (SLOF) (Schneider and week 1 for aripiprazole. Dosage adjustments occurred in Struening, 1983), Barratt Impulsiveness Scale 11-item step-wise increments or decrements of 1 mg for brexpi- (BIS-11) (Patton et al., 1995), and Cogstate computerized prazole and 5 mg for aripiprazole. Dosage increases were cognitive test battery (Nuechterlein et al., 2008) score for only allowed at scheduled visits, whereas decreases could the early phase battery [comprising the following tasks: have occurred at any time during the trial following the Groton Maze Learning Task (reasoning and problem week 1 visit. Adjustments were made on the basis of the solving), Detection Task (speed of processing), clinical judgment of the investigator. To ensure a uni- Identification Task (attention/vigilance), and One Card form level of background cognitive function, patients Learning Task (visual learning)]; cognitive test battery with a cognitive test battery composite score up to − 0.5 score for every battery task [comprising all early phase (mild cognitive impairment or worse in severity) at tasks and the following additional tasks: One-Back baseline and patients with a composite score more than Memory Task (working memory); Two-Back Memory − 0.5 at baseline were randomized to each treatment Task (working memory); Social Emotional Cognition group in equal distributions. Randomization was Test (emotional processing); and the International achieved using the interactive voice response system or Shopping List Task (verbal learning and memory)]. the interactive web response system. The baseline visit Assessments at week 6 included Clinical Global occurred no later than 21 days after the date of hospital Impressions-Improvement Scale (CGI-I) score (Guy, admission. All patients were followed up by telephone to 1976) and response rate [defined as reduction of 30% or evaluate safety at 30 (+ 2) days after the last dose of study more from baseline in PANSS total score, or CGI-I score medication. of 1 (very much improved) or 2 (much improved)]. An Patient consent was required for study participation and overview of timing of the efficacy and safety assessments the study was carried out in compliance with the can be found in Supplementary Table 1 (Supplemental International Conference on Harmonization Good digital content 1, http://links.lww.com/ICP/A17). Raters Brexpiprazole and aripiprazole in acute schizophrenia Citrome et al. 195 were trained on the administration of each of the efficacy Table 1 Patient dispositions assessments. Brexpiprazole [n (%)] Aripiprazole [n (%)] Safety and tolerability assessments included AEs; the Randomized 64 33 Treated 64 (100.0) 33 (100.0) following EPS scales: Simpson Angus Scale (Simpson Completed 40 (62.5) 21 (63.6) and Angus, 1970), Abnormal Involuntary Movement Discontinued 24 (37.5) 12 (36.4) Scale (Guy, 1976), and the Barnes Akathisia Rating Scale Patient withdrew consent 14 (21.9) 4 (12.1) Lost to follow-up 3 (4.7) 5 (15.2) (BARS) (Barnes, 1989); body weight; laboratory tests; Patient fulfilled the withdrawal 4 (6.3) 1 (3.0) vital signs; Columbia Suicide Severity Rating Scale criteria (Posner et al., 2011); and ECGs. Adverse events 3 (4.7) 1 (3.0) Patient withdrawn by 0 (0.0) 1 (3.0) investigator Statistical analysis Analyzed for safety (safety analysis 64 (100.0) 33 (100.0) set)a Analysis sets included safety analysis set (all patients who Analyzed for efficacy (full analysis 64 (100.0) 33 (100.0) took at least one dose of study medication) and full set)b analysis set (all randomized patients who underwent a aAll patients who received at least one dose of study medication were included in baseline assessment, took at least one dose of study the safety analysis. medication, and who underwent at least one postbaseline bAll patients who received at least one dose of study medication and who underwent a baseline assessment and at least one postbaseline efficacy efficacy assessment). assessment were included in full efficacy analysis. As all patients received study medication and there were no protocol violations, the safety analysis set and the full A total of 45 (70.3%) patients were exposed to brexpi- analysis set included the same patient population. A prazole for between 35 and 41 days, with a mean daily mixed model repeated measures analysis was used to dose of 3.58 mg (range: 2–4 mg). A total of 21 (63.6%) investigate change from baseline in efficacy, including patients were exposed to aripiprazole for 35–41 days, cognitive function (cognitive test battery composite with a mean daily dose of 18.20 mg (range: 10–20 mg). score), using a two-sided significance level of 0.05. The model included fixed effects of visit and baseline PANSS Patient demographics were similar in the two treatment total score/cognitive test battery composite score, and an groups, with a majority of patients being men and Black interaction term of baseline PANSS total score/cognitive or African American (Table 2). test battery composite score by visit. The imputation of missing data using mixed model repeated-measure was Efficacy findings based on the observed case dataset. The last-observation- Within-group improvements in PANSS total score from carried-forward dataset included data recorded at a baseline to week 6 were observed for both brexpiprazole scheduled treatment phase visit or, if no observation was and aripiprazole (Table 3); the least squares (LS) mean recorded at that visit, data carried forward from the pre- improvement observed at week 6 was − 22.9 points for vious scheduled treatment phase visit. An analysis of brexpiprazole (P < 0.0001 vs. baseline) and − 19.4 points covariance was carried out on the last-observation- for aripiprazole (P < 0.0001 vs. baseline; Fig. 2). carried-forward dataset. As this was an exploratory study, correction for multiple comparisons between groups was not performed. AEs were coded by system Table 2 Patient demographics organ class and preferred term using the Medical Brexpiprazole Aripiprazole Dictionary for Regulatory Activities 17.0 (MedDRA). (n = 64) (n = 33) Age [mean (SD)] (years) 42.2 (10.1) 42.1 (10.4) Results Weight [mean (SD)] (kg) 89.9 (19.7) 87.2 (18.3) Height [mean (SD)] (cm) 173.1 (9.0) 173.5 (9.8) Patients BMI [mean (SD)] (kg/m2) 30.2 (7.4) 29.1 (6.2) A total of 97 patients were randomized, with 64 patients Sex [n (%)] Male 46 (71.9) 23 (69.7) receiving brexpiprazole and 33 patients receiving aripi- Female 18 (28.1) 10 (30.3) prazole. A total of 61 (62.9%) patients completed the Race [n (%)] study, 40 (62.5%) in the brexpiprazole group and 21 White 14 (21.9) 8 (24.2) Black or African American 48 (75.0) 24 (72.7) (63.6%) in the aripiprazole group (Table 1). The most Asian 1 (1.6) 0 (0.0) common reason for discontinuation was ‘patient with- Other 1 (1.6) 1 (3.0) ’ Ethnicity [n (%)] drew consent [18/36 (50%) of the discontinued partici- Hispanic/Latino 7 (10.9) 2 (6.1) pants; 14 (21.9%) from the brexpiprazole group and four Not Hispanic/Latino 57 (89.1) 30 (90.9) (12.1%) from the aripiprazole group]. Overall, four (4.1%) Other 0 (0.0) 1 (3.0) Age at first diagnosis for 25.6 (9.2) 22.8 (9.3) patients were withdrawn because of AEs: three (4.7%) schizophrenia [mean (SD)] patients in the brexpiprazole group (possible seizure, (years) schizophrenia, and facial nerve paralysis) and one (3.0%) Duration of current episode [mean 4.1 (3.1) 4.0 (3.0) (SD)] (weeks) in the aripiprazole group (presyncope). 196 International Clinical Psychopharmacology 2016, Vol 31 No 4

Table 3 Summary of efficacy results at week 6 Improvements in PANSS total score were observed as < Brexpiprazole (n = 64) Aripiprazole (n = 33) early as week 1 in both treatment groups (P 0.0001 and P = 0.0005 for brexpiprazole and aripiprazole, PANSS total scorea Mean (SD) value at baseline 94.1 (10.1) 93.3 (9.6) respectively). LS mean (SE) change at week − 22.9 (1.7) − 19.4 (2.4) 6 Clinically relevant improvements from baseline in psy- CGI-S scorea chopathology were observed for both brexpiprazole and Mean (SD) value at baseline 5.0 (0.7) 4.8 (0.8) LS mean (SE) change at week − 1.6 (0.1) − 1.3 (0.2) aripiprazole (Fig. 2 and Table 3). Brexpiprazole showed a 6 slightly greater numerical improvement compared with CGI-I scoreb Mean (SD) value at week 6 2.5 (0.9) 2.7 (1.0) aripiprazole in a number of measures of psychopathology Response rateb and patient function (CGI-S, SLOF, and BIS-11 scores; Proportion (%) of responders 39 (60.9) 16 (48.5) Table 3). Improvements in the CGI-S score from base- at week 6 95% CI 47.9–72.9 30.8–66.5 line to week 6 were observed for the brexpiprazole and SLOF total scoreb aripiprazole groups (Table 3). The LS mean improve- Mean (SD) value at baseline 111.9 (14.5) 112.2 (14.6) Mean (SD) change at week 6 7.7 (14.8) 5.5 (11.3) ment in CGI-S observed from baseline at week 6 was 95% CI 4.0–10.9 1.2–10.8 − 1.6 points for the brexpiprazole group (P < 0.0001) and BIS-11 total scoreb − 1.3 points for the aripiprazole group (P < 0.0001). Mean (SD) value at baseline 70.4 (10.9) 71.3 (9.4) Mean (SD) change at week 6 − 2.7 (10.0) 0.1 (6.9) Improvements in the CGI-S score, supporting the 95% CI − 5.0 to − 0.1 − 3.5–3.3 PANSS results, were observed as early as week 1 in both < = BIS-11, Barratt Impulsiveness Scale 11-item; CGI-I, Clinical Global Impression- treatment groups (P 0.0001 and P 0.0114, for brexpi- Improvement Scale; CGI-S, Clinical Global Impression-Severity of Illness Scale; prazole and aripiprazole, respectively). The mean (SD) CI, confidence interval; LS, least squares; PANSS, Positive and Negative CGI-I scores improved with each subsequent measure- Syndrome Scale; SE, standard error; SLOF, Specific Levels of Functioning Scale. aMixed model repeated-measure analysis. ment, with a score at week 6 of 2.5 (0.9) for brexpiprazole bLast-observation-carried-forward. and 2.7 (1.0) for aripiprazole. The CGI-I score is based on changes from the initiation of treatment, with a score of 2 indicating a much improved status and a score of 3 indicating a minimally improved status. The response rate [defined as a reduction of ≥ 30% from Fig. 2 baseline in PANSS total score or CGI-I score of 1 (very much improved) or 2 (much improved) at week 6] was 0 higher in the brexpiprazole group (60.9%) compared with −4 the aripiprazole group (48.5%; Table 3). Increases in the −8 mean SLOF total score from baseline were observed at week 6 [from 111.9 at baseline to 119.5 at week 6 in the −12 <

CI) change in brexpiprazole group (P 0.0001), and from 112.2 at

% −16 baseline to 118.9 at week 6 in the aripiprazole group (P = 0.0158); Table 3]. Improvements from baseline at −20

PANSS total score week 6 were observed for all four areas of the SLOF −24 score with brexpiprazole and for two areas with aripipra- LS mean (95 zole. Mean (SD) change from baseline at week 6 for −28 interpersonal relationships was 2.0 (5.5) for the brexpi- 0123456 prazole group and 1.1 (3.9) for the aripiprazole group Weeks (P = 0.0065 and 0.0824, respectively). In social accept- Brexpiprazole (1−4 mg/day; target dose 3 mg/day; n = 64) ability, the mean (SD) change from baseline at week 6 Aripiprazole (10−20 mg/day; target dose 15 mg/day; n = 33) was 0.7 (2.4) and 0.0 (2.1) for the brexpiprazole = = Mean change from baseline in PANSS total scores. P = 0.0005 versus (P 0.0223) and aripiprazole (P 0.8201) groups, baseline for aripiprazole at week 1 and P = 0.0001 versus baseline at all respectively. The mean (SD) change from baseline at other time points for both treatment groups. PANSS total baseline scores: brexpiprazole, 94.1; aripiprazole, 93.3. All brexpiprazole-treated week 6 in activities was 2.8 (7.6) for the brexpiprazole patients were initiated at 1 mg/day, with dose adjustments ranging from group (P = 0.0045) and 2.6 (6.8) for the aripiprazole group 1–4 mg, and a targeted titration of 3 mg at the week 1 visit. All (P = 0.0450). Finally, the mean (SD) change from base- aripiprazole-treated patients were initiated at 10 mg/day, with a dose adjustment ranging from 10–20 mg, and a targeted titration of 15 mg at line at week 6 in work skills was 2.2 (4.8) for the brex- the week 1 visit. Shaded area represents the study titration period. LS piprazole group (P = 0.0002) and 1.8 (4.0) for the − mean change from baseline to week 6: brexpiprazole: 22.9 (95% CI aripiprazole group (P = 0.0486). − 26.2 to − 19.6), P < 0.0001 versus baseline; aripiprazole: − 19.4 (95% CI − 24.1 to − 14.6), P < 0.0001 versus baseline. All data represent mixed model repeated measures analysis. CI, confidence A 3.84% reduction from baseline in impulsivity, as interval; LS, least squares; PANSS, Positive and Negative Syndrome Scale. assessed by the BIS-11 total score, was observed with brexpiprazole at week 6. In the aripiprazole group, there Brexpiprazole and aripiprazole in acute schizophrenia Citrome et al.197 was a 0.14% increase in the BIS-11 total score, which Table 4 Treatment-emergent adverse events reported in 5% or indicates a small increase in impulsivity from baseline to more of patients week 6. The mean (SD) change in impulsivity from TEAEs Brexpiprazole (n = 64) [n (%)] Aripiprazole (n = 33) [n (%)] baseline at week 6 was − 2.7 (10.0) for brexpiprazole Akathisia 6 (9.4) 7 (21.2) (P = 0.0392) and 0.1 (6.9) for aripiprazole (P = 0.9716; Weight increase 6 (9.4) 3 (9.1) Headache 5 (7.8) 4 (12.1) Table 3). Dyspepsia 5 (7.8) 3 (9.1) Dry mouth 5 (7.8) 2 (6.1) Nausea 4 (6.3) 1 (3.0) Cognitive test battery scores Pain in extremity 4 (6.3) 1 (3.0) No worsening of cognitive function was observed for the Constipation 3 (4.7) 3 (9.1) brexpiprazole group on any of the cognitive tests, Diarrhea 3 (4.7) 2 (6.1) Back pain 2 (3.1) 2 (6.1) whereas the aripiprazole group worsened on the Two- Sedation 0 (0.0) 2 (6.1) Back Memory Task. The LS mean change from baseline Muscle spasms 0 (0.0) 2 (6.1) for the cognitive test battery composite score at week 6 Toothache 0 (0.0) 2 (6.1) was 0.045 for brexpiprazole and − 0.024 for aripiprazole, TEAE, treatment-emergent adverse event. indicating no change in cognitive functioning in either group (Fig. 3). For the early phase cognitive test battery brexpiprazole group were akathisia (9.4%) and weight scores, the LS mean change from baseline was not significant for the brexpiprazole (− 0.010) or aripiprazole increase (9.4%), and for the aripiprazole group, akathisia (0.113) groups. Of the eight tasks performed by patients, (21.2%) and headache (12.1%) were reported. a greater improvement was observed in the brexpiprazole Interestingly, fewer patients from the brexpiprazole group group for the One-Back Memory Task (P = 0.0048) and a experienced at least one headache (7.8% vs. 12.1%) numerical decline was observed in the aripiprazole group TEAE. All TEAEs were mild or moderate in severity. A for the Two-Back Memory Task (P = 0.0007). total of 19 patients experienced EPS-related TEAEs during the study; brexpiprazole had a lower incidence of Safety findings EPS-related AEs compared with aripiprazole (14.1% vs. Adverse events 30.3%). The incidence of EPS-related TEAEs can be A similar percentage of patients in the brexpiprazole seen in Table 5. It was notable that the incidence of both (57.8%) and aripiprazole (63.6%) groups reported at least akathisia and EPS-related AEs was higher in patients one treatment-emergent adverse event (TEAE). treated with aripiprazole compared with brexpiprazole (absolute risk increases of 11.8% and 16.2%, respectively). The most frequently reported TEAEs (reported by 5% or more patients in either group) are presented in Table 4. No deaths occurred during this study. A total of four The most frequently reported TEAEs in the (4.1%) patients [three (4.7%) in the brexpiprazole group and one (3.0%) in the aripiprazole group] experienced Fig. 3 serious adverse events (SAEs) during the study. For the 0.2 brexpiprazole group, these included a worsening of schizophrenia paranoid type (leading to discontinuation), 0.1 a possible seizure (leading to discontinuation), and an acute hepatitis B infection, and in the aripiprazole group, 0.0 one participant reported an episode of presyncope that CI) change in resulted in discontinuation. Although one participant in % −0.1 the brexpiprazole group had an episode of facial paralysis that led to discontinuation, this was not considered an composite score −0.2 SAE or treatment related. LS mean (95 −0.3 0123456Table 5 Incidence of extrapyramidal symptom-related treatment- Weeks emergent adverse events = = Brexpiprazole (1–4 mg/day; target dose 3 mg/day; n = 64) Brexpiprazole (n 64) Aripiprazole (n 33) Aripiprazole (10–20 mg/day; target dose 15 mg/day; n = 33) TEAEs [n (%)] [n (%)] Any EPS-event 9 (14.1) 10 (30.3) Akathisia events 6 (9.4) 7 (21.2) Mean change from baseline in cognitive test battery composite score. Parkinsonian events 2 (3.1) 1 (3.0) All changes from baseline were minimal. Cognitive test battery Dystonic events 1 (1.6) 2 (6.1) composite baseline scores: brexpiprazole, − 0.015; aripiprazole, Residual events 0 (0.0) 0 (0.0) 0.174. All data represent mixed model repeated measures analysis. Dyskinetic events 0 (0.0) 0 (0.0) CI, confidence interval; LS, least squares. EPS, extrapyramidal symptom; TEAE, treatment-emergent adverse event. 198 International Clinical Psychopharmacology 2016, Vol 31 No 4

Extrapyramidal symptoms patients in the brexpiprazole group and 19% (4/21) of Mean (SD) change from baseline at week 6 was not patients in the aripiprazole group. Further characteriza- clinically meaningful for Simpson Angus Scale [0.1 (1.3) tion of these patients with potentially clinically relevant and 0.0 (1.0) for brexpiprazole and aripiprazole, respec- weight increase indicated that 4/14 (28.6%) patients from tively], Abnormal Involuntary Movement Scale [0.0 (0.4) the brexpiprazole group and 2/4 (50.0%) patients from and 0.1 (0.4) for brexpiprazole and aripiprazole, respec- the aripiprazole group had a body mass index of 27 or tively], or BARS global clinical assessment of akathisia more at baseline (Supplementary Table 2, Supplemental [0.0 (0.6) and 0.0 (0.8) for brexpiprazole and aripiprazole, digital content 1, http://links.lww.com/ICP/A17). One respectively] scores. patient from the aripiprazole group was reported to show potentially clinically relevant (≥7%) weight loss. No patients were reported to have moderate to severe Supplementary Table 3 (Supplemental digital content 1, akathisia at baseline. One patient in the aripiprazole http://links.lww.com/ICP/A17) provides additional infor- group had moderate to severe akathisia at week 6 as mation on the three patients with the greatest weight assessed by the BARS global clinical assessment of gain or weight loss for both brexpiprazole and aripipra- akathisia. zole treatment groups. No clinically relevant changes were observed in the mean Body weight and metabolic parameters change from baseline to week 6 in metabolic parameters The rate of spontaneously reported weight increase was for either drug (Table 6). similar in both groups: 9.4% for brexpiprazole and 9.1% for aripiprazole. Mean changes in body weight and Suicidality body mass index at week 6 showed a similar profile for There were no TEAEs related to suicidal behavior brexpiprazole and aripiprazole (see Table 6 and reported in the study. The Columbia Suicide Severity Supplementary Fig. 1, Supplemental digital content 1, Rating Scale results indicated the emergence of suicidal http://links.lww.com/ICP/A17). A potentially clinically ideation in two patients and, in addition, the worsening of ≥ relevant weight gain (defined as 7% increase from suicidal ideation in two further patients in the baseline) at week 6 was observed in 35% (14/40) of brexpiprazole group.

Table 6 Mean changes in body weight, BMI, fasting metabolic Prolactin parameters, and prolactin from baseline to week 6 The overall mean change from baseline for both male Brexpiprazole (n = 64) Aripiprazole (n = 33) and female patients was small (Table 6) and similar for Assessments [mean (SD)] [mean (SD)] both treatment groups. Body weight (kg) Baseline body weight 89.9 (19.7) 87.2 (18.3) Electrocardiograms Change in body weight 4.3 (4.3) 3.8 (5.5) BMI (kg/m2) The mean changes from baseline at week 6 for all ECG Baseline BMI 30.2 (7.4) 29.1 (6.2) parameters were minimal and none were considered to Change in BMI 1.4 (1.4) 1.2 (1.7) Fasting metabolic parameters (mg/dl) be clinically meaningful; no patients experienced a new- Cholesterol onset QTc more than 450 ms and one patient in the Baseline cholesterol 190.9 (40.4) 197.4 (42.8) brexpiprazole group experienced an increase of 30–60 ms Change in cholesterol − 3.0 (23.9) − 3.8 (24.6) HDL cholesterol in the QTcF (399 ms at baseline and 442 ms at dis- Baseline HDL 54.5 (12.9) 54.8 (15.0) continuation). In the aripiprazole group, one patient cholesterol experienced an SAE of moderate presyncope with clini- Change in HDL − 4.6 (9.0) − 0.7 (13.4) cholesterol cally significant ECG findings and was discontinued from LDL cholesterol the study. Baseline LDL 113.1 (31.8) 118.1 (38.1) cholesterol Change in LDL 0.8 (20.9) − 4.5 (18.1) Discussion cholesterol In this randomized, open-label, exploratory study, clini- Triglycerides Baseline triglycerides 115.4 (64.7) 125.6 (75.8) cally relevant improvements in symptoms of schizo- Change in triglycerides 3.9 (43.9) 0.3 (48.3) phrenia were observed in patients with acute Glucose Baseline glucose 94.9 (8.8) 97.8 (19.0) schizophrenia treated with brexpiprazole (target dose of Change in glucose 2.3 (17.5) 3.2 (13.1) 3 mg) or aripiprazole (target dose of 15 mg). Prolactin (ng/ml) Females Improvements in the PANSS total score, supported by Baseline prolactin 18.1 (21.6) 8.3 (6.7) the CGI-S and CGI-I results, were observed as early as Change in prolactin − 0.6 (16.9) 0.6 (5.0) Males week 1 in both treatment groups. The early improve- Baseline prolactin 8.4 (5.8) 9.9 (7.2) ments observed for a number of the efficacy measures − Change in prolactin 0.4 (5.8) 4.2 (2.6) suggest that both brexpiprazole and aripiprazole may HDL, high-density lipoprotein; LDL, low-density lipoprotein. have a rapid onset of action even when patients are being Brexpiprazole and aripiprazole in acute schizophrenia Citrome et al.199 titrated to their target dose. The degree of improvement in this study were similar to those reported in other trials in scales of psychiatric symptoms is clinically meaningful with brexpiprazole (Citrome, 2015a, 2015b; Correll et al., and suggests that both drug treatments produce clinically 2015; Kane et al., 2015). The incidence of TEAE-related relevant improvements in psychopathology. Although discontinuations because of either study medication was the efficacy of aripiprazole has been well documented comparable with other studies (Croxtall, 2012). No over time (Kane et al., 2002; Croxtall, 2012), the present clinically meaningful changes in laboratory parameters or findings, together with data collected from two pivotal vital signs were observed, confirming the clinically trials (Correll et al., 2015; Kane et al., 2015), suggest that acceptable tolerability profile for both FDA-approved brexpiprazole is at least comparable with aripiprazole in drugs (Otsuka Pharmaceutical Co. Ltd, 2015, 2016). terms of efficacy for the treatment of schizophrenia. The increase in spontaneously reported body weight as a In addition, improvements in the patient-rated SLOF TEAE in 9.4% of patients in the brexpiprazole group and total score were observed at week 6 in both treatment 9.1% in the aripiprazole group over 6 weeks warrants groups. The SLOF is a 30-item scale that measures further discussion. The mean weight change from base- practical aspects of everyday function with four domains: line to week 6 was comparable between brexpiprazole interpersonal relationships (seven items), social accept- (4.3 kg) and aripiprazole (3.8 kg), with a similar pattern of ability (six items), activities (11 items), and work skill (six change in weight at week 6 for both treatment groups items) (Schneider and Struening, 1983). The brexpipra- (see Supplementary Fig. 1, Supplemental digital content zole group showed improvements, as indicated by an 1, http://links.lww.com/ICP/A17). These values appear to increased SLOF total score, on all four domains, whereas be larger than those documented previously in pivotal the aripiprazole group showed improvements on two phase III studies (Correll et al., 2015; Kane et al., 2015). domains: activities and work skills. Considering the limits The incidence of weight increase 7% or more was dis- of comparative assessments, given the small sample and proportionately higher in the brexpiprazole group open-label design of the present study, it is notable that (35.0%) than in the aripiprazole group (19.0%) relative to the brexpiprazole group showed significant improve- the mean change. It is interesting to note that there was a ments compared with baseline on interpersonal rela- disproportionately high randomization of Black/African tionships and social acceptability, whereas the American patients (74%). In a short-term study of adult aripiprazole group did not. patients with schizophrenia administered aripiprazole once monthly (Kane et al., 2014), there was a similar high In this study, the mean changes from baseline in percentage (66%, 110/168) of patients who were Black/ impulsivity scores were small. However, reductions in African American and the incidence of clinically mean- impulsivity scores as measured by BIS-11 were observed ingful weight increase (≥7%) was 21.5% (31/144) (Kane with brexpiprazole, with no change being observed for et al., 2014). It is possible that Black/African American aripiprazole, suggesting improvements in impulsive per- patients are more prone to antipsychotic-induced weight sonality traits in the brexpiprazole group, but not in the increases, which may be because of genetics (Carliner aripiprazole group. As improvements are based on a trait et al., 2014). Weight gain is a common problem with scale, the clinical significance of a 3 percentage-point atypical antipsychotic agents, and any weight gain must difference is difficult to interpret. Interestingly, the mean be balanced against the clinical benefits that patients scores in both groups were 70.4 and 71.3 for the brexpi- experience with a given agent. Metabolic monitoring in prazole and aripiprazole groups, respectively, which schizophrenic patients taking antipsychotics is recom- suggests a relatively high level of baseline impulsivity in mended as routine by the American Psychiatric both groups. Impulsivity is associated with worse treat- Association to ensure that weight gain is not accompanied ment outcomes in patients with schizophrenia as beha- by changes in metabolic parameters, such as increased vioral manifestations of impulsivity include agitation, cholesterol or triglycerides (Dixon et al., 2010). Clinically aggression, hostility, substance abuse, and risky beha- relevant changes in metabolic parameters were not viors (Citrome, 2007). observed during this study for either brexpiprazole or No meaningful worsening in cognitive function was aripiprazole. observed in either treatment group. The greater In addition to metabolic side effects, EPS-related side improvement observed in the brexpiprazole group for the effects are the other main concern when using anti- One-Back Memory Task (P = 0.0048) and numerical psychotics. Here, the percentage of EPS-related AEs in decline observed in the aripiprazole group for the Two- the aripiprazole group was twice that of the brexpiprazole Back Memory Task (P = 0.0007) may be because of group [10 (30.3%) and nine (14.1%) patients, respec- chance as no correction for multiple tests was performed. tively]. The EPS-related difference was largely because Brexpiprazole was well tolerated, as indicated by low of the rates of akathisia being two times higher in the rates of discontinuation because of AEs. In general, the aripiprazole group (21.2% compared with 9.4% in the types and frequency of TEAEs, TEAEs related to EPSs, brexpiprazole group). The lower rates of EPS-related SAEs, and discontinuations because of TEAEs reported TEAEs with brexpiprazole could relate to its higher 200 International Clinical Psychopharmacology 2016, Vol 31 No 4

affinity at serotonin 5-HT2A receptors, providing a and Development Inc. (Princeton, New Jersey, USA) and potentially more balanced occupancy of brexpiprazole H. Lundbeck A/S (Valby, Denmark). across D2 and 5-HT2A receptors than aripiprazole (Maeda α et al., 2014a). In addition, antagonism of the 1 adrenergic Conflicts of interest receptor has also been implicated in reduced rates of In the past 36 months, Leslie Citrome has acted as a akathisia (Stahl, 2013) and the brexpiprazole affinity at consultant for Alexza, Alkermes, Allergan, Avanir, α the 1b receptor is more than 10 times higher than that Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, observed with aripiprazole (Citrome, 2013; Maeda et al., Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, 2014a). Taken together, the lower intrinsic activity at the Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, D2 receptor of brexpiprazole compared with aripiprazole Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, (Maeda et al., 2014b) and the unique serotonergic and Teva, Valeant, and Vanda. In the past 36 months, Leslie noradrenergic receptor footprint of brexpiprazole may Citrome has received speaking fees from Alkermes, partly explain the lower rates of EPS-related side effects Allergan AstraZeneca, Janssen, Jazz, Lundbeck, Merck, found in the present study. Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and The limitations of this study need to be considered when Teva. Leslie Citrome has stocks (small number of shares interpreting the results, including the nature of the open- of common stock) in Bristol-Myers Squibb, Eli Lilly, label design and the fact that both participants and Johnson & Johnson, Merck, and Pfizer. All were pur- researchers, including raters, were aware of which treat- chased more than 10 years ago. Ai Ota and Kazuhiro ment was being administered. Although participants Nagamizu are employees of Otsuka Pharmaceutical were randomized to receive either brexpiprazole or ari- Co. Ltd. Pamela Perry and Ross A. Baker are employees piprazole irrespective of their demographics, concomitant of Otsuka Pharmaceutical Development & Commer- medications, or disease history, expectation bias may cialization Inc. Emmanuelle Weiller is an employee of H. have been present. In addition, aripiprazole was included Lundbeck A/S. for validation of the sensitivity of the cognitive assay and not as an active comparator arm. Taken together, References numerical differences in rates of EPS-related side effects Barnes TR (1989). A rating scale for drug-induced akathisia. Br J Psychiatry = 154:672–676. [number needed to harm 7 for brexpiprazole vs. aripi- Blier P, Ward NM (2003). 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