Schizophrenia is a chronic and debilitating mental illness (Volavka and Citrome, 2009). Individuals with schizophrenia experience a range of impairments, including positive (e.g. hallucinations, delusions), negative (e.g. social withdrawal, lack of emotion, apathy), and cognitive (e.g. memory, attention, problem solving) symptoms (Volavka and Citrome, 2009; Levi et al., 2013). Another symptom domain of schizophrenia includes impulsive behaviors, agitation, and hostility (Citrome, 2007; Ouzir, 2013; Reddy et al., 2014). Schizophrenia not only has a profound detrimental effect on the patient’s well-being and ability to function in society but also a cost burden of more than $62 billion per year in the USA (Saha et al., 2005; Wu et al., 2005; Volavka and Citrome, 2009).
Schizophrenia, in general, remains a complex and difficult-to-treat disorder, despite the number of different antipsychotics commercially available (Volavka and Citrome, 2009; Citrome, 2013). Meta-analyses have shown that when comparing groups of patients enrolled in clinical trials, first-line second-generation antipsychotics can differ considerably in reported side effects, with smaller differences observed in efficacy (De Hert et al., 2012a; Citrome, 2013; Leucht et al., 2013; Citrome and Volavka, 2014). Importantly, efficacy and tolerability responses to different antipsychotics can vary markedly among individual patients in clinical practice (Citrome, 2013).
Antipsychotic drugs bind to a variety of dopaminergic, serotonergic, noradrenergic, histaminic, and muscarinic receptors. Their affinity and intrinsic activity for the D2 receptor varies, with effective blockade being achieved at different dose levels, often resulting in drug concentrations that can lead to the blockade of other receptor systems, potentially triggering associated side effects (Correll, 2010). The different receptor-binding profiles of current second-generation antipsychotics may contribute toward the variability in accompanying side effects (Correll, 2010), including weight gain, sedation, restlessness/agitation, akathisia, QTc prolongation, extrapyramidal symptoms (EPSs), and hyperprolactinemia (and associated sexual effects) (Kane et al., 2010; De Hert et al., 2012b; Leucht et al., 2013). Therefore, selection of an effective antipsychotic for a patient requires careful consideration of the agent’s full efficacy and safety profile (Citrome and Volavka, 2014). Antipsychotic treatment selection requires the careful balancing of activating and sedating side effects, as well as minimizing the risk for EPSs, metabolic, and cardiovascular events associated with various antipsychotic agents.
Brexpiprazole (OPC-34712) is a serotonin-dopamine activity modulator (Maeda et al., 2014a). It acts as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at 5-HT2A and noradrenaline α1B/2C receptors (Maeda et al., 2014a), with similar affinity at all 5 receptors. As reward capacity can be diminished by pure D2 full antagonists, partial D2 agonists may preserve reward capacity mediated by D2 receptors and thus contribute toward improved patient functioning and autonomy (Stahl, 2008). Both brexpiprazole and aripiprazole (available commercially since 2002) are second-generation antipsychotics that act as partial agonists at D2 and serotonin 5-HT1A receptors and as antagonists at the 5-HT2A receptor (Shapiro et al., 2003; Maeda et al., 2014a). However, aripiprazole has been associated with inducing D2 agonist-mediated adverse events (AEs) such as akathisia, insomnia, restlessness, agitation, and nausea (Fleischhacker, 2005; Otsuka Pharmaceutical Co. Ltd, 2016).
Brexpiprazole has a lower intrinsic activity at the D2 receptor than aripiprazole, and as such should induce fewer D2 agonist-mediated AEs. In addition, brexpiprazole has a higher affinity at the 5-HT2A receptor than aripiprazole and as 5-HT2A antagonism may reduce D2 antagonist-induced akathisia (Laoutidis and Luckhaus, 2014), brexpiprazole may have the potential to be associated with fewer EPS-related events compared with aripiprazole. Brexpiprazole also shows higher affinity for the 5-HT1A receptor than aripiprazole, which could have potential benefits on depressive symptoms common in patients with schizophrenia (Blier and Ward, 2003; Celada et al., 2004; Maeda et al., 2014b). Higher affinity at the α1 adrenergic receptor for brexpiprazole than aripiprazole may also mitigate against EPS-related effects (Stahl, 2013), and may also be useful in managing agitation and sleep disturbances. The α1 antagonist prazosin, for example, has been shown to improve agitation associated with Alzheimer’s disease (Wang et al., 2009) and hyperarousal/sleep disturbances associated with post-traumatic stress syndrome (De Berardis et al., 2015). Brexpiprazole has shown robust effects on positive symptoms and cognitive impairment in relevant animal models, with superior effects in cognitive tests compared with those of aripiprazole (Maeda et al., 2014b). Furthermore, brexpiprazole showed statistically significant efficacy and good tolerability compared with placebo in two recent phase III clinical studies in adult patients with acute schizophrenia (Correll et al., 2015; Kane et al., 2015). Systematic clinical reviews can be found elsewhere (Citrome, 2015a, 2015b).
The aim of this open-label study (ClinicalTrials.gov NCT02054702) was to explore changes in efficacy, cognitive functioning, and safety of a 6-week treatment with flexibly-dosed brexpiprazole or aripiprazole monotherapy in patients with schizophrenia. Aripiprazole was included as a positive control to confirm assay sensitivity in this study.
Patients and methods
Adult patients (18–65 years old) with a Diagnostic and statistical manual of mental disorders, 4th ed., text revision (DSM-IV-TR) diagnosis of schizophrenia that was confirmed by the Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders (Sheehan et al., 1998) were recruited to participate. Patients were eligible if, in the investigator’s opinion, they might potentially benefit from hospitalization or continued hospitalization with brexpiprazole or aripiprazole monotherapy for the treatment of a current acute relapse of schizophrenia. Patients had to be experiencing an acute exacerbation of psychotic symptoms and marked deterioration of usual function as shown by all of the following: Positive and Negative Syndrome Scale (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 hallucinatory behavior, unusual thought content, conceptual disorganization, or suspiciousness; and Clinical Global Impression-Severity of Illness Scale (CGI-S) score 4 or more (moderately ill). Patients were excluded if they were presenting with a first episode of schizophrenia, had been hospitalized for more than 21 days for the current acute episode, had a current DSM-IV-TR Axis 1 diagnosis other than schizophrenia, or they showed an improvement of 20% or more in the total PANSS score between the screening and the baseline assessments.
This was a 6-week, phase IIIb, exploratory, open-label, multicenter, flexible-dose study in adult patients carried out between 27 February 2014 and 25 July 2014 at 19 sites across the USA.
The study consisted of a 2–14-day screening phase to assess eligibility and to wash out previous antipsychotic medications and any prohibited concomitant medications, a 6-week treatment phase in which patients were randomly assigned 2 : 1 to receive brexpiprazole or aripiprazole, and a 30-day follow-up phase (Fig. 1). Once informed consent was obtained, all participants were hospitalized up to at least the week 2 study visit after the initiation of active treatment. Eligible patients received flexible dosages of open-label brexpiprazole (1–4 mg/day) or aripiprazole (10–20 mg/day) starting at 1 mg/day and titrating to a target dosage of 3 mg/day at the end of week 1 for brexpiprazole, and starting at 10 mg/day and titrating to a target dosage of 15 mg/day at the end of week 1 for aripiprazole. Dosage adjustments occurred in step-wise increments or decrements of 1 mg for brexpiprazole and 5 mg for aripiprazole. Dosage increases were only allowed at scheduled visits, whereas decreases could have occurred at any time during the trial following the week 1 visit. Adjustments were made on the basis of the clinical judgment of the investigator. To ensure a uniform level of background cognitive function, patients with a cognitive test battery composite score up to −0.5 (mild cognitive impairment or worse in severity) at baseline and patients with a composite score more than −0.5 at baseline were randomized to each treatment group in equal distributions. Randomization was achieved using the interactive voice response system or the interactive web response system. The baseline visit occurred no later than 21 days after the date of hospital admission. All patients were followed up by telephone to evaluate safety at 30 (+2) days after the last dose of study medication.
Patient consent was required for study participation and the study was carried out in compliance with the International Conference on Harmonization Good Clinical Practice Guidelines, and applicable local laws and regulatory requirements.
The efficacy outcomes included changes from baseline to week 6 in PANSS total score, CGI-S score, Specific Levels of Functioning Scale (SLOF) (Schneider and Struening, 1983), Barratt Impulsiveness Scale 11-item (BIS-11) (Patton et al., 1995), and Cogstate computerized cognitive test battery (Nuechterlein et al., 2008) score for the early phase battery [comprising the following tasks: Groton Maze Learning Task (reasoning and problem solving), Detection Task (speed of processing), Identification Task (attention/vigilance), and One Card Learning Task (visual learning)]; cognitive test battery score for every battery task [comprising all early phase tasks and the following additional tasks: One-Back Memory Task (working memory); Two-Back Memory Task (working memory); Social Emotional Cognition Test (emotional processing); and the International Shopping List Task (verbal learning and memory)]. Assessments at week 6 included Clinical Global Impressions-Improvement Scale (CGI-I) score (Guy, 1976) and response rate [defined as reduction of 30% or more from baseline in PANSS total score, or CGI-I score of 1 (very much improved) or 2 (much improved)]. An overview of timing of the efficacy and safety assessments can be found in Supplementary Table 1 (Supplemental digital content 1, http://links.lww.com/ICP/A17). Raters were trained on the administration of each of the efficacy assessments.
Safety and tolerability assessments included AEs; the following EPS scales: Simpson Angus Scale (Simpson and Angus, 1970), Abnormal Involuntary Movement Scale (Guy, 1976), and the Barnes Akathisia Rating Scale (BARS) (Barnes, 1989); body weight; laboratory tests; vital signs; Columbia Suicide Severity Rating Scale (Posner et al., 2011); and ECGs.
Analysis sets included safety analysis set (all patients who took at least one dose of study medication) and full analysis set (all randomized patients who underwent a baseline assessment, took at least one dose of study medication, and who underwent at least one postbaseline efficacy assessment).
As all patients received study medication and there were no protocol violations, the safety analysis set and the full analysis set included the same patient population. A mixed model repeated measures analysis was used to investigate change from baseline in efficacy, including cognitive function (cognitive test battery composite score), using a two-sided significance level of 0.05. The model included fixed effects of visit and baseline PANSS total score/cognitive test battery composite score, and an interaction term of baseline PANSS total score/cognitive test battery composite score by visit. The imputation of missing data using mixed model repeated-measure was based on the observed case dataset. The last-observation-carried-forward dataset included data recorded at a scheduled treatment phase visit or, if no observation was recorded at that visit, data carried forward from the previous scheduled treatment phase visit. An analysis of covariance was carried out on the last-observation-carried-forward dataset. As this was an exploratory study, correction for multiple comparisons between groups was not performed. AEs were coded by system organ class and preferred term using the Medical Dictionary for Regulatory Activities 17.0 (MedDRA).
A total of 97 patients were randomized, with 64 patients receiving brexpiprazole and 33 patients receiving aripiprazole. A total of 61 (62.9%) patients completed the study, 40 (62.5%) in the brexpiprazole group and 21 (63.6%) in the aripiprazole group (Table 1). The most common reason for discontinuation was ‘patient withdrew consent’ [18/36 (50%) of the discontinued participants; 14 (21.9%) from the brexpiprazole group and four (12.1%) from the aripiprazole group]. Overall, four (4.1%) patients were withdrawn because of AEs: three (4.7%) patients in the brexpiprazole group (possible seizure, schizophrenia, and facial nerve paralysis) and one (3.0%) in the aripiprazole group (presyncope).
A total of 45 (70.3%) patients were exposed to brexpiprazole for between 35 and 41 days, with a mean daily dose of 3.58 mg (range: 2–4 mg). A total of 21 (63.6%) patients were exposed to aripiprazole for 35–41 days, with a mean daily dose of 18.20 mg (range: 10–20 mg).
Patient demographics were similar in the two treatment groups, with a majority of patients being men and Black or African American (Table 2).
Within-group improvements in PANSS total score from baseline to week 6 were observed for both brexpiprazole and aripiprazole (Table 3); the least squares (LS) 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; Fig. 2). Improvements in PANSS total score were observed as early as week 1 in both treatment groups (P<0.0001 and P=0.0005 for brexpiprazole and aripiprazole, respectively).
Clinically relevant improvements from baseline in psychopathology were observed for both brexpiprazole and aripiprazole (Fig. 2 and Table 3). Brexpiprazole showed a slightly greater numerical improvement compared with aripiprazole in a number of measures of psychopathology and patient function (CGI-S, SLOF, and BIS-11 scores; Table 3). Improvements in the CGI-S score from baseline to week 6 were observed for the brexpiprazole and aripiprazole groups (Table 3). The LS mean improvement in CGI-S observed from baseline at week 6 was −1.6 points for the brexpiprazole group (P<0.0001) and −1.3 points for the aripiprazole group (P<0.0001). Improvements in the CGI-S score, supporting the PANSS results, were observed as early as week 1 in both treatment groups (P<0.0001 and P=0.0114, for brexpiprazole and aripiprazole, respectively). The mean (SD) CGI-I scores improved with each subsequent measurement, with a score at week 6 of 2.5 (0.9) for brexpiprazole 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 baseline in PANSS total score or CGI-I score of 1 (very much improved) or 2 (much improved) at week 6] was higher in the brexpiprazole group (60.9%) compared with the aripiprazole group (48.5%; Table 3). Increases in the mean SLOF total score from baseline were observed at week 6 [from 111.9 at baseline to 119.5 at week 6 in the brexpiprazole group (P<0.0001), and from 112.2 at baseline to 118.9 at week 6 in the aripiprazole group (P=0.0158); Table 3]. Improvements from baseline at week 6 were observed for all four areas of the SLOF score with brexpiprazole and for two areas with aripiprazole. Mean (SD) change from baseline at week 6 for interpersonal relationships was 2.0 (5.5) for the brexpiprazole group and 1.1 (3.9) for the aripiprazole group (P=0.0065 and 0.0824, respectively). In social acceptability, the mean (SD) change from baseline at week 6 was 0.7 (2.4) and 0.0 (2.1) for the brexpiprazole (P=0.0223) and aripiprazole (P=0.8201) groups, respectively. The mean (SD) change from baseline at week 6 in activities was 2.8 (7.6) for the brexpiprazole group (P=0.0045) and 2.6 (6.8) for the aripiprazole group (P=0.0450). Finally, the mean (SD) change from baseline at week 6 in work skills was 2.2 (4.8) for the brexpiprazole group (P=0.0002) and 1.8 (4.0) for the aripiprazole group (P=0.0486).
A 3.84% reduction from baseline in impulsivity, as assessed by the BIS-11 total score, was observed with brexpiprazole at week 6. In the aripiprazole group, there was a 0.14% increase in the BIS-11 total score, which indicates a small increase in impulsivity from baseline to week 6. The mean (SD) change in impulsivity from baseline at week 6 was −2.7 (10.0) for brexpiprazole (P=0.0392) and 0.1 (6.9) for aripiprazole (P=0.9716; Table 3).
Cognitive test battery scores
No worsening of cognitive function was observed for the brexpiprazole group on any of the cognitive tests, whereas the aripiprazole group worsened on the Two-Back Memory Task. The LS mean change from baseline for the cognitive test battery composite score at week 6 was 0.045 for brexpiprazole and −0.024 for aripiprazole, indicating no change in cognitive functioning in either group (Fig. 3). For the early phase cognitive test battery scores, the LS mean change from baseline was not significant for the brexpiprazole (−0.010) or aripiprazole (0.113) groups. Of the eight tasks performed by patients, a greater improvement was observed in the brexpiprazole group for the One-Back Memory Task (P=0.0048) and a numerical decline was observed in the aripiprazole group for the Two-Back Memory Task (P=0.0007).
A similar percentage of patients in the brexpiprazole (57.8%) and aripiprazole (63.6%) groups reported at least one treatment-emergent adverse event (TEAE).
The most frequently reported TEAEs (reported by 5% or more patients in either group) are presented in Table 4. The most frequently reported TEAEs in the brexpiprazole group were akathisia (9.4%) and weight increase (9.4%), and for the aripiprazole group, akathisia (21.2%) and headache (12.1%) were reported. Interestingly, fewer patients from the brexpiprazole group experienced at least one headache (7.8% vs. 12.1%) TEAE. All TEAEs were mild or moderate in severity. A total of 19 patients experienced EPS-related TEAEs during the study; brexpiprazole had a lower incidence of EPS-related AEs compared with aripiprazole (14.1% vs. 30.3%). The incidence of EPS-related TEAEs can be seen in Table 5. It was notable that the incidence of both akathisia and EPS-related AEs was higher in patients treated with aripiprazole compared with brexpiprazole (absolute risk increases of 11.8% and 16.2%, respectively).
No deaths occurred during this study. A total of four (4.1%) patients [three (4.7%) in the brexpiprazole group and one (3.0%) in the aripiprazole group] experienced serious adverse events (SAEs) during the study. For the brexpiprazole group, these included a worsening of schizophrenia paranoid type (leading to discontinuation), a possible seizure (leading to discontinuation), and an acute hepatitis B infection, and in the aripiprazole group, one participant reported an episode of presyncope that resulted in discontinuation. Although one participant in the brexpiprazole group had an episode of facial paralysis that led to discontinuation, this was not considered an SAE or treatment related.
Mean (SD) change from baseline at week 6 was not clinically meaningful for Simpson Angus Scale [0.1 (1.3) and 0.0 (1.0) for brexpiprazole and aripiprazole, respectively], Abnormal Involuntary Movement Scale [0.0 (0.4) and 0.1 (0.4) for brexpiprazole and aripiprazole, respectively], or BARS global clinical assessment of akathisia [0.0 (0.6) and 0.0 (0.8) for brexpiprazole and aripiprazole, respectively] scores.
No patients were reported to have moderate to severe akathisia at baseline. One patient in the aripiprazole group had moderate to severe akathisia at week 6 as assessed by the BARS global clinical assessment of akathisia.
Body weight and metabolic parameters
The rate of spontaneously reported weight increase was similar in both groups: 9.4% for brexpiprazole and 9.1% for aripiprazole. Mean changes in body weight and body mass index at week 6 showed a similar profile for brexpiprazole and aripiprazole (see Table 6 and Supplementary Fig. 1, Supplemental digital content 1, http://links.lww.com/ICP/A17). A potentially clinically relevant weight gain (defined as ≥7% increase from baseline) at week 6 was observed in 35% (14/40) of patients in the brexpiprazole group and 19% (4/21) of patients in the aripiprazole group. Further characterization of these patients with potentially clinically relevant weight increase indicated that 4/14 (28.6%) patients from the brexpiprazole group and 2/4 (50.0%) patients from the aripiprazole group had a body mass index of 27 or more at baseline (Supplementary Table 2, Supplemental digital content 1, http://links.lww.com/ICP/A17). One patient from the aripiprazole group was reported to show potentially clinically relevant (≥7%) weight loss. Supplementary Table 3 (Supplemental digital content 1, http://links.lww.com/ICP/A17) provides additional information on the three patients with the greatest weight gain or weight loss for both brexpiprazole and aripiprazole treatment groups.
No clinically relevant changes were observed in the mean change from baseline to week 6 in metabolic parameters for either drug (Table 6).
There were no TEAEs related to suicidal behavior reported in the study. The Columbia Suicide Severity Rating Scale results indicated the emergence of suicidal ideation in two patients and, in addition, the worsening of suicidal ideation in two further patients in the brexpiprazole group.
The overall mean change from baseline for both male and female patients was small (Table 6) and similar for both treatment groups.
The mean changes from baseline at week 6 for all ECG parameters were minimal and none were considered to be clinically meaningful; no patients experienced a new-onset QTc more than 450 ms and one patient in the brexpiprazole group experienced an increase of 30–60 ms in the QTcF (399 ms at baseline and 442 ms at discontinuation). In the aripiprazole group, one patient experienced an SAE of moderate presyncope with clinically significant ECG findings and was discontinued from the study.
In this randomized, open-label, exploratory study, clinically relevant improvements in symptoms of schizophrenia were observed in patients with acute schizophrenia treated with brexpiprazole (target dose of 3 mg) or aripiprazole (target dose of 15 mg).
Improvements in the PANSS total score, supported by the CGI-S and CGI-I results, were observed as early as week 1 in both treatment groups. The early improvements observed for a number of the efficacy measures suggest that both brexpiprazole and aripiprazole may have a rapid onset of action even when patients are being titrated to their target dose. The degree of improvement in scales of psychiatric symptoms is clinically meaningful and suggests that both drug treatments produce clinically relevant improvements in psychopathology. Although the efficacy of aripiprazole has been well documented over time (Kane et al., 2002; Croxtall, 2012), the present findings, together with data collected from two pivotal trials (Correll et al., 2015; Kane et al., 2015), suggest that brexpiprazole is at least comparable with aripiprazole in terms of efficacy for the treatment of schizophrenia.
In addition, improvements in the patient-rated SLOF total score were observed at week 6 in both treatment groups. The SLOF is a 30-item scale that measures practical aspects of everyday function with four domains: interpersonal relationships (seven items), social acceptability (six items), activities (11 items), and work skill (six items) (Schneider and Struening, 1983). The brexpiprazole group showed improvements, as indicated by an increased SLOF total score, on all four domains, whereas the aripiprazole group showed improvements on two domains: activities and work skills. Considering the limits of comparative assessments, given the small sample and open-label design of the present study, it is notable that the brexpiprazole group showed significant improvements compared with baseline on interpersonal relationships and social acceptability, whereas the aripiprazole group did not.
In this study, the mean changes from baseline in impulsivity scores were small. However, reductions in impulsivity scores as measured by BIS-11 were observed with brexpiprazole, with no change being observed for aripiprazole, suggesting improvements in impulsive personality traits in the brexpiprazole group, but not in the aripiprazole group. As improvements are based on a trait scale, the clinical significance of a 3 percentage-point difference is difficult to interpret. Interestingly, the mean scores in both groups were 70.4 and 71.3 for the brexpiprazole and aripiprazole groups, respectively, which suggests a relatively high level of baseline impulsivity in both groups. Impulsivity is associated with worse treatment outcomes in patients with schizophrenia as behavioral manifestations of impulsivity include agitation, aggression, hostility, substance abuse, and risky behaviors (Citrome, 2007).
No meaningful worsening in cognitive function was observed in either treatment group. The greater improvement observed in the brexpiprazole group for the One-Back Memory Task (P=0.0048) and numerical decline observed in the aripiprazole group for the Two-Back Memory Task (P=0.0007) may be because of chance as no correction for multiple tests was performed.
Brexpiprazole was well tolerated, as indicated by low rates of discontinuation because of AEs. In general, the types and frequency of TEAEs, TEAEs related to EPSs, SAEs, and discontinuations because of TEAEs reported in this study were similar to those reported in other trials with brexpiprazole (Citrome, 2015a, 2015b; Correll et al., 2015; Kane et al., 2015). The incidence of TEAE-related discontinuations because of either study medication was comparable with other studies (Croxtall, 2012). No clinically meaningful changes in laboratory parameters or vital signs were observed, confirming the clinically acceptable tolerability profile for both FDA-approved drugs (Otsuka Pharmaceutical Co. Ltd, 2015, 2016).
The increase in spontaneously reported body weight as a TEAE in 9.4% of patients in the brexpiprazole group and 9.1% in the aripiprazole group over 6 weeks warrants further discussion. The mean weight change from baseline to week 6 was comparable between brexpiprazole (4.3 kg) and aripiprazole (3.8 kg), with a similar pattern of change in weight at week 6 for both treatment groups (see Supplementary Fig. 1, Supplemental digital content 1, http://links.lww.com/ICP/A17). These values appear to be larger than those documented previously in pivotal phase III studies (Correll et al., 2015; Kane et al., 2015). The incidence of weight increase 7% or more was disproportionately higher in the brexpiprazole group (35.0%) than in the aripiprazole group (19.0%) relative to the mean change. It is interesting to note that there was a disproportionately high randomization of Black/African American patients (74%). In a short-term study of adult patients with schizophrenia administered aripiprazole once monthly (Kane et al., 2014), there was a similar high percentage (66%, 110/168) of patients who were Black/African American and the incidence of clinically meaningful weight increase (≥7%) was 21.5% (31/144) (Kane et al., 2014). It is possible that Black/African American patients are more prone to antipsychotic-induced weight increases, which may be because of genetics (Carliner et al., 2014). Weight gain is a common problem with atypical antipsychotic agents, and any weight gain must be balanced against the clinical benefits that patients experience with a given agent. Metabolic monitoring in schizophrenic patients taking antipsychotics is recommended as routine by the American Psychiatric Association to ensure that weight gain is not accompanied by changes in metabolic parameters, such as increased cholesterol or triglycerides (Dixon et al., 2010). Clinically relevant changes in metabolic parameters were not observed during this study for either brexpiprazole or aripiprazole.
In addition to metabolic side effects, EPS-related side effects are the other main concern when using antipsychotics. Here, the percentage of EPS-related AEs in the aripiprazole group was twice that of the brexpiprazole group [10 (30.3%) and nine (14.1%) patients, respectively]. The EPS-related difference was largely because of the rates of akathisia being two times higher in the aripiprazole group (21.2% compared with 9.4% in the brexpiprazole group). The lower rates of EPS-related TEAEs with brexpiprazole could relate to its higher affinity at serotonin 5-HT2A receptors, providing a potentially more balanced occupancy of brexpiprazole across D2 and 5-HT2A receptors than aripiprazole (Maeda et al., 2014a). In addition, antagonism of the α1 adrenergic receptor has also been implicated in reduced rates of akathisia (Stahl, 2013) and the brexpiprazole affinity at the α1b receptor is more than 10 times higher than that observed with aripiprazole (Citrome, 2013; Maeda et al., 2014a). Taken together, the lower intrinsic activity at the D2 receptor of brexpiprazole compared with aripiprazole (Maeda et al., 2014b) and the unique serotonergic and noradrenergic receptor footprint of brexpiprazole may partly explain the lower rates of EPS-related side effects found in the present study.
The limitations of this study need to be considered when interpreting the results, including the nature of the open-label design and the fact that both participants and researchers, including raters, were aware of which treatment was being administered. Although participants were randomized to receive either brexpiprazole or aripiprazole irrespective of their demographics, concomitant medications, or disease history, expectation bias may have been present. In addition, aripiprazole was included for validation of the sensitivity of the cognitive assay and not as an active comparator arm. Taken together, numerical differences in rates of EPS-related side effects [number needed to harm=7 for brexpiprazole vs. aripiprazole; calculation: 1/(rate with brexpiprazole−rate with aripiprazole) (Citrome, 2009; Citrome and Ketter, 2013)], PANSS responder rates (number needed to treat= 9 for brexpiprazole vs. aripiprazole), mean change in BIS-11 scores, and mean change in social function domains of SLOF all provide signals that the different pharmacologic footprint of brexpiprazole compared with aripiprazole may have a clinically meaningful effect. As the assessment of clinical effects here is based on the magnitude of difference between the randomized groups, adequately powered, head-to-head comparative studies are required to fully understand the differences between brexpiprazole and aripiprazole.
The results of the present phase IIIb, exploratory, multicenter, randomized, open-label, flexible-dose study in adult patients with acute schizophrenia indicate that brexpiprazole could provide similar efficacy to aripiprazole in the treatment of the symptoms of schizophrenia, with the potential for some benefits on behavioral manifestations of impulsivity and social functional, and a relatively favorable tolerability profile with respect to akathisia and other EPS-related side effects.
The authors thank the patients who participated in this study. Rachel Cicchelli, PhD [QXV Communications, an Ashfield business (part of UDG Healthcare Plc), Macclesfield, UK], provided writing support that was funded by Otsuka Pharmaceutical Commercialization and Development Inc. (Princeton, New Jersey, USA) and H. Lundbeck A/S (Valby, Denmark).
Conflicts of interest
In the past 36 months, Leslie Citrome has acted as a consultant for Alexza, Alkermes, Allergan, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, Valeant, and Vanda. In the past 36 months, Leslie Citrome has received speaking fees from Alkermes, Allergan AstraZeneca, Janssen, Jazz, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva. Leslie Citrome has stocks (small number of shares of common stock) in Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer. All were purchased more than 10 years ago. Ai Ota and Kazuhiro Nagamizu are employees of Otsuka Pharmaceutical Co. Ltd. Pamela Perry and Ross A. Baker are employees of Otsuka Pharmaceutical Development & Commercialization Inc. Emmanuelle Weiller is an employee of H. Lundbeck A/S.
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