Research Article
`
`For reprint orders, please contact: reprints@futuremedicine.com
`
`Efficacy and metabolic effects of
`lurasidone versus brexpiprazole in
`schizophrenia: a network meta-analysis
`
`Daisy Ng-Mak*,1, Vanita Tongbram2, Kerigo Ndirangu2, Krithika Rajagopalan1 &
`Antony Loebel3
`1Sunovion Pharmaceuticals, Inc., Marlborough, MA 01752, USA
`2ICON Health Economics, New York, NY 10017, USA
`3Sunovion Pharmaceuticals, Inc., Fort Lee, NJ 07024, USA
`*Author for correspondence: Tel.: +1 774 369 7010; daisy.ng-mak@sunovion.com
`
`Aim: To assess the relative efficacy and metabolic effects of lurasidone and brexpiprazole in the acute
`treatment of schizophrenia. Methods: Five lurasidone and three brexpiprazole trials were identified. In the
`absence of head-to-head trials, a Bayesian network meta-analysis comparing lurasidone and brexpipra-
`zole was performed. Results: Nonstatistically significant differences in efficacy measures were observed
`between lurasidone and brexpiprazole. Significant differences favoring lurasidone for weight change (-
`0.69 kg; 95% CrI: -1.22 to -0.15), total cholesterol (-7.60 mg/dl; 95% CrI: -13.94 to -1.22), and low-density
`lipoprotein (-6.58 mg/dl; 95% CrI: -12.11 to -1.04) were observed, with a trend indicating half the risk of
`experiencing ≥7% weight gain. Conclusion: This network meta-analysis suggested that lurasidone had
`similar efficacy and fewer metabolic effects than brexpiprazole in patients with acute schizophrenia.
`
`First draft submitted: 15 February 2018; Accepted for publication: 12 April 2018; Published online:
`26 April 2018
`Keywords: atypical antipsychotics • brexpiprazole • lurasidone • network meta-analysis • schizophrenia • weight
`gain
`
`The lifetime prevalence of schizophrenia, one of the most debilitating and expensive chronic psychiatric disorders,
`is 0.5–1.0% [1,2]. Patients with schizophrenia experience incapacitating symptoms such as hallucinations, delusions
`and disorganized thinking that can compromise normal daily activities [3]. Antipsychotic medications are the first-
`line treatment of schizophrenia during acute episodes, when the primary goal is to reduce the severity of psychosis
`and associated symptoms, as well as during the stable phase, when the goals are to maximize functioning and
`prevent relapses [4,5].
`Adherence often remains sub-optimal in schizophrenia due in part to the difficulty of finding a treatment that
`is both efficacious and tolerable for a given patient [6–8]. Identifying an antipsychotic that balances efficacy and
`tolerability could improve treatment adherence, thereby lowering the risk of relapse and hospitalization [9]. A large
`network meta-analysis that incorporated 212 schizophrenia clinical trials and examined 15 different antipsychotics
`demonstrated that there are small but consistent differences in efficacy, with clozapine appearing to be the most
`efficacious [10]. However, treatments clearly differed on tolerability attributes, with extrapyramidal symptoms and
`weight gain being two primary areas of concern [10].
`Atypical antipsychotics are generally preferred over typical antipsychotics because of their lower risk for extrapyra-
`midal symptoms [11]. However, some atypicals are associated with negative metabolic changes such as weight gain
`and adverse changes in cholesterol and triglyceride levels [12]. Weight gain, as well as other metabolic effects, may
`increase treatment discontinuations. In a large 3-year observational study of 7728 patients with schizophrenia, only
`39.7% stayed on their prescribed antipsychotic for the entire study period, and among patients who discontinued
`their antipsychotic medications, 38.7% discontinued due to lack of efficacy, and 14.2% discontinued due to toler-
`ability issues [13]. In a clinical effectiveness trial, among 1432 patients who received their randomized antipsychotic,
`only 25.9% stayed on treatment for the full 18-months, with 23.7% discontinuing due to lack of efficacy and
`14.9% due to lack of tolerability [6].
`
`10.2217/cer-2018-0016 C(cid:2) 2018 Sunovion Pharmaceuticals Inc.
`
`J. Comp. Eff. Res. (2018) 7(8), 737–748
`
`ISSN 2042-6305
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`737
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`1
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`Slayback v. Sumitomo
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`Research Article
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`Ng-Mak, Tongbram, Ndirangu, Rajagopalan & Loebel
`
`Both efficacy and tolerability appear to play an important role in the discontinuation rates for antipsychotics.
`Patients with schizophrenia are at greater risk of developing diabetes and cardiovascular disease and some atyp-
`ical antipsychotics appear to increase these risks [14,15]. When examining patient concerns about antipsychotics
`in a patient preference study, treatment-induced weight gain was the third greatest concern for patients with
`schizophrenia, after improvement in symptoms and elimination of hyperglycemia [16]. Reducing weight gain and
`the associated cardiometabolic changes may improve treatment adherence [8] and patient outcomes. Even relatively
`small differences in treatment adherence have been linked to a lower risk of hospitalization [9].
`The National Association of State Mental Health Program Directors recognized that antipsychotics are not
`interchangeable and recommend including at least one weight-neutral treatment on formulary for those patients
`with potential metabolic issues [17]. Successful treatment for the majority of patients with schizophrenia involves
`balancing the benefits and risks of antipsychotics, with clozapine being the last resort treatment for refractory
`patients [17]. Due to the complexity of successfully managing schizophrenia, an individualized treatment for
`schizophrenia which is based on the patient’s needs and preference should be considered [17–19].
`Two atypical antipsychotics that had a low incidence of weight gain in a large meta-analysis were lurasidone and
`aripiprazole [10]. Preclinical studies indicate that lurasidone has a high affinity for dopamine receptor D2 and the
`serotonin receptor 5-HT2A, and little to no affinity for histaminergic receptors [20]. In contrast, preclinical studies
`indicate that aripiprazole is a partial D2 agonist, with high affinity for 5-HT2A and modest H1 binding [21]. In the
`meta-analysis, both lurasidone and aripiprazole had a low risk for weight gain, and similar levels of improvement
`in symptoms, rates of all-cause discontinuation and rates of sedation [10].
`Brexpiprazole, approved by the US FDA in 2015, has a similar binding profile to aripiprazole as a partial D2
`agonist with moderate histamine binding, but with a higher affinity for serotonin receptor 5-HT2A [22]. In a clinical
`trial that directly compared aripiprazole and brexpiprazole, both had similar efficacy, similar rates of weight gain
`reported as an adverse event (aripiprazole 9.4% and brexpiprazole 9.1%), but aripiprazole-treated patients were
`more likely to have extrapyramidal symptoms (21.2 vs 9.4%) [23]. As aripiprazole and lurasidone have comparable
`efficacy and weight gain rates, examining if brexpiprazole has similar results when compared with lurasidone would
`be of interest for patients that are particularly vulnerable to metabolic changes.
`Currently, there are no head-to-head clinical trials comparing the efficacy and metabolic parameters of lurasidone
`and brexpiprazole. Given that both of these antipsychotics appear to be relatively weight neutral atypical antipsy-
`chotics, evidence is needed to assist physicians and formulary decision makers in understanding potential differences
`between them. This study, using a network meta-analysis, summarized the relative efficacy and metabolic effects of
`lurasidone and brexpiprazole based on acute randomized clinical trials in adults with schizophrenia.
`
`Methods
`Literature search & selection
`A systematic literature review was conducted using the Preferred Reporting Items for Systematic Reviews and
`Meta-Analyses (PRISMA) statement, aligned with the Centre for Reviews and Dissemination guide for conducting
`systematic reviews [24,25], and informed by the Population, Intervention, Comparison, Outcome and Study (PI-
`COS) type framework [26]. Randomized controlled trials that included lurasidone and brexpiprazole (Phase II, III
`and IV trials) for adult populations (≥18 years old) with schizophrenia were identified. Searches were conducted
`in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and PubMed in November 2015. In
`addition, proceedings from Schizophrenia International Research Society Conference and the proceedings from
`the American Psychiatric Association conference were searched from 2013 through the third quarter of 2015. Only
`articles in English were included. Randomized clinical trials were restricted to those using at least one arm with the
`FDA-approved doses of lurasidone (40–160 mg/day) or brexpiprazole (2–4 mg/day). The review was restricted to
`clinical trials assessing the efficacy of the medications in reducing symptoms during acute episodes of schizophrenia.
`See Supplementary Information for further details on the literature search.
`
`Network meta-analysis
`A network meta-analysis of lurasidone and brexpiprazole randomized clinical trials for acute treatment of schizophre-
`nia was conducted using a Bayesian framework in WinBUGS1.4. The framework used guidelines from the National
`Institute for Health and Care Excellence Decision Support Unit Technical Support Guidance [27]. Using placebo as
`the common comparator, the analysis compared the efficacy and the tolerability of lurasidone and brexpiprazole.
`For trials with multiple fixed dose arms, the arms with FDA-approved doses were pooled.
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`The primary efficacy outcome measure was response rate, defined as≥20% improvement in Positive and Negative
`Syndrome Scale (PANSS). Secondary efficacy outcome measures included change from baseline in PANSS and
`change from baseline in Clinical Global Impressions-Severity Scale (CGI-S) scores. Metabolic outcomes included
`the proportion with clinically significant weight gain (i.e., ≥7% increase in weight) and changes from baseline
`in the following parameters: weight, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein
`(HDL), and triglycerides.
`For continuous outcomes, median difference in change from baseline over 6 weeks was estimated along with the
`95% credible interval (CrI). CrIs are the Bayesian equivalent of confidence intervals. For dichotomous outcomes,
`a logit model estimated the odds ratio (OR) and 95% CrI. Results were considered significant if the 95% CrI did
`not include zero for continuous outcome variables or one for dichotomous outcome variables.
`Following the recommendation of the International Society for Pharmacoeconomics and Outcomes Research
`(ISPOR) task force [28], a vague prior distribution was used where any parameter value was equally likely. Simulation
`convergence was evaluated from history, trace plots, and Brooks–Gelman–Rubin convergence statistics model
`diagnostics from 40,000 iterations with additional iterations used when diagnostics suggested sufficient convergence
`was not achieved [29,30].
`The goodness-of-fit for each model was evaluated using the Deviance Information Criterion (DIC) score, with a
`lower DIC score indicating a better fitting model. The DIC provides an estimate of model fit that is penalized for
`increased model complexity [31]. All outcome variables were assessed using both fixed and random effects models.
`The fixed effects models generally had a better fit and were reported here. Results of the random effect models are
`available upon request.
`
`Results
`Study selection
`The systematic literature review identified a total of 419 citations. After removing duplicates and abstract screening,
`50 publications (full text and conference abstracts) were included. Of these, 14 were primary publications (10
`lurasidone and four brexpiprazole). Figure 1 summarizes the selection and review process.
`Within the ten lurasidone trials, six trials assessed outcomes for acute schizophrenia [32–37]. Four other lurasidone
`trials [38–41] were excluded from the review because they included only stable patients. One acute trial for lurasidone,
`OPTIMIZE [36], was subsequently excluded from the analysis due to its unique study design which involved a
`nested randomization of patients not having an early response to a higher dose of lurasidone.
`Within the brexpiprazole trials, three trials assessing acute episodes of schizophrenia [23,42,43] were included
`and one trial [44] was excluded from the review as it was in stable patients. Among the 14 primary lurasidone
`and brexpiprazole publications, eight trials met all the selection criteria: five for lurasidone [32–35,37] and three for
`brexpiprazole [23,42,43].
`
`Trial heterogeneity
`Trial heterogeneity for every treatment arm using an FDA-approved dose was assessed by examining distribution of
`the trial baseline characteristics. These characteristics were plotted by drug to assess whether suitably comparable
`patients were included across the trials available for pooling.
`Table 1 presents the baseline characteristics across trials, with weighted averages for the fixed-dose trials that
`had multiple treatment arms. All eight studies had reasonably comparable baseline characteristics and appeared
`appropriate to include in the network meta-analysis: mean age ranged from 37.0 to 42.2 years, percent of females
`ranged from 16.0 to 38.7%, mean age of symptom onset ranged from 23.3 to 27.4, mean BMI ranged from 25.7 to
`31.2, mean PANSS ranged from 91.2 to 97.2, and mean CGI-S ranged from 4.8 to 5.0. Table 2 gives the outcome
`measures from each trial at the end of 6 weeks. Not all trials measured all variables. The relative homogeneity of
`patients and outcomes across the trials, along with the DIC values, appeared consistent with fixed effects model
`assumptions.
`
`Network meta-analysis results
`Forest plots of results for efficacy and metabolic measures are presented in Figures 2 & 3, respectively. For the
`efficacy variables, there were no significant differences based on the 95% CrIs. Although not statistically significant,
`lurasidone was associated with a higher likelihood of treatment response (OR: 1.28; 95% CrI: 0.88–1.87) and
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`Lurasidone versus brexpiprazole in schizophrenia
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`

`Researd'r Article
`
`Ng—Mak, Tongbram, Ndirangu, Rajagopalan & Loebel
`
`
`
`figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
`
`greater improvements (median changes) for both PANSS (-2.48; CrI: -6.39—l.46) and CGI-S (-0.14; 95% Cr]:
`-0.35—0.07) than brexpiprazole (Figure 2).
`The fixed effects models showed significant differences in metabolic outcomes favoring lurasidone for less weight
`gain (-0.69 kg; 95% Cd -l.22 to -0.15), total cholesterol (-7.60 mg/dl; 95% Cd: 43.94 to -l.22) and [BL (-
`6.58 mg/dl; 95% Cr]: -l2.l l to 4.04). There was also a nonsignificant trend showing lurasidone patients were half
`as likely to experience clinically signifimnt (27%) weight gain (OR: 0.50; 95% Cr]: 0.22-1.07) (Figure 3). Both
`fixed and random effects models produced directionally similar estimates for all eflicacy and metabolic outcomes,
`with random effects modd yielding wider Cris fix the estimates that were not statistically significant.
`
`Discussion
`
`The results from this network men-analysis indicate that lurasidone was associated with similar improvements
`in eflicacy compared with hrexpipramle. However, the results also demonstrated that lurasidone was associated
`with significantly lower weight gain compared with brexpiprazole, with an average difierence of -0.69 kg, after 6
`weeks. Longer-term head-to-hcad trials are needed to estimate potential diEermces in long-term weight change
`and clinical implications and relevance ofthis finding.
`Brexpiprazole is a partial D2 agonist with a similar molecular structure [22] and clinical profile to aripiprazole [23].
`When lurasidone and aripiprazole were compared in an earlier network meta-analysis, eflicacy was similar, but
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`Lurasidone versus brexpiprazole in schizophrenia
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`
`® Response rate
`
`I
`
`
`Favors brexpiprazole
`:
`Favors Iurasidone
`
`1.28 (0.88—1.87)
`
`I '
`
`l
`
`0
`0.5
`1
`1.5
`2
`
`Odds ratio (95% Crl)
`
`PANSS
`
`‘—
`Favors Iurasidone
`
`l
`
`:
`I
`
`
`Favors brexpiprazole
`
`|
`-2.48 (6.39—1.46)
`l—o—r—l
`l
`
`-8
`-6
`-4
`-2
`0
`2
`4
`6
`8
`
`Median dflerenee (95% Crl)
`
`© cars
`
`l
`
`<— —>
`Favors Iurasidone
`:
`Favors brexpiprazole
`I
`
`-o.14 (0.35-0.07)
`
`-O.5
`-0.25
`0
`0.25
`0.5
`
`'I
`
`Median dilemma (95% Crl)
`
`Figure 2. Forest plots comparing Iurasidone with brexpiprazole on efficacy measures: results of the network
`meta-analysis. Data were from the fixed effect models. Error bars represent the 95% Crl. Response was defined as a
`220% improvement in PANSS.
`Crl: Credible interval; CGl-S: Clinical Global Impressions — Severity; PANSS: Positive and Negative Syndrome Scale.
`
`Iurasidone was associated with a nonsignificant greater reduction in weight gain [IO]. Although variability in
`efficacy across atypical antipsychoties is generally low with the possible exception of clozapine, there are significant
`differences in tolerability [Io]. Comparisons between Iurasidone and brexpiprazole in the current network meta—
`analysis were largely consistent with these earlier findings comparing Iurasidone and aripiprazole: similar eflicacy,
`but with Iurasidone associated with significantly less weight gain than brexpiprazole.
`As most atypical antipsychotics are associated with weight gain [45], the National Association of State Mental
`Health Program Directors recommended that patients have access to at least one weight-neutral prescribing
`option [17]. Studies with Iurasidone have consistently indicated a potentially more favorable weight gain profile
`compared with other antipsydlotics. In a pooled analysis ofsix Iurasidone clinical trials in schizophrenia that were at
`least 12—months in length, Iurasidone-treated patients had lower rates of clinically significant weight gain compared
`with patients treated with risperidone or quetiapine [46]. Similarly, in usual clinical care, a study ofelectronic medical
`records found that the patients who gained weight on their previous antipsychotic subsequently lost weight after
`switching to Iurasidone [47].
`Reducing weight gain may help prevent cardiovascular disease [14] and reduce negative cardiometabolic changes
`such as increased cholesterol levels and glucose levels [48]. Some atypical antipsychotics appear to increase the risk
`of developing diabetes and cardiovascular disease in patients with schizophrenia [14,15]. This analysis found that
`Iurasidone was associated with significantly greater reductions in total cholesterol and LDL levels compared with
`
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`Ng-Mak. Tongbram, Ndirangu, Rajagopalan & Loebel
`
`@ Weimt change
`
`
`
`Favors lurasidone Favors brexpiprazole
`
`~0.69 (-1.22, -o.15)
`l—O—I
`
`.2
`-1
`0
`1
`2
`Median difference (95% Cd)
`
`Weight gain (27%)
`
`
`
`Favors lurasidone Favors brexpiprazole
`
`I I I I
`
`l
`0.50 (0.22—1.07)
`l—O—I—l
`
` 0
`
`0.5
`
`1
`
`1.5
`
`2
`
`Odds ratio (95% Crl)
`
`© Carliovascular risk factors
`
`Favors lurasidone.— Favors brexpiprazole
`
`Total cholesterol
`
`-260 (-13.94, 4.22)
`l—O—l
`
`LDL
`
`HDL
`
`-6.58 (-12.11, -1.o4)
`|—.—|
`-1.81 (-3.77—0.16)
`I—O—l
`-o.9o (-16.12-14.39)'
`
`-24
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`-20
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`-16
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`-12
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`-8
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`-4
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`0
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`4
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`8
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`12
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`16
`
`20
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`24
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`Median difference (95% Cll)
`
`Figure 3. Forest plots comparing lurasidone and brexpiprazole on metabolic measures: results of the network
`meta-analysis. Error bars represent file 95% Crl. Cholesterol and triglycerides were measured in mg/dl. Lower OR on
`clinically significant weight gain (27%) indicate a lower risk for lurasidone than brexpiprazole. Negative median
`differences on weight change and cardiovascular risk factors indicate greater reductions for lurasidone than
`brexpiprazole.
`Crl: Credible interval; HDL: High-density Iipoprotein; LDL: Low-density Iipoprotein; OR: Odd ratio.
`
`patients treated with brexpiprazole. Prior research suggests that a relatively modest weight loss Ge, 5%) may lead to
`improvement in cardiometabolic parameters [49]. Treatment adherence may be improved by minimizing weight gain
`and potentially improving cardiometabolic measures [8] and patient outcomes. The findings of reduced weight gain
`and improvements in eardiometabolic parameters with the use oflurasidone instead ofbrexpiprazole corroborate this
`previous research about the potential relationship between weight gain and atrdiometabolic disease. A prescribing
`option with reasonable efficacy that does not significantly increase the risk of developing or exacerbating common
`metabolic disorders in the patients with schizophrenia could be particularly helpful for this patient population.
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`Limitations
`Given that brexpiprazole is a recently approved atypical antipsychotic, a systematic literature search identified only
`three brexpiprazole randomized clinical trials that were suitable for inclusion in the network meta-analysis. The
`majority (12/13) of randomized clinical trials were designed and statistically powered to compare the treatment to
`the placebo, not for head-to-head comparisons in a network meta-analysis. The analysis only included randomized
`clinical trials, which have rigorous patient selection and study oversight, further observational research is needed to
`verify the findings generalize to real-world settings. The lack of statistical significance in some of the analyses does
`not indicate that meaningful differences do not exist, only that there was insufficient statistical power to identify
`the differences. The clinical relevance of weight difference and changes in cholesterol over a longer-time period
`remain unclear and need further study. Although glucose was not analyzed in this study, if differences exist they
`most likely would not have manifested in the 6-week-time period.
`This network meta-analysis did not include a 6-week, double-blind, placebo- and haloperidol-controlled Phase
`II study of lurasidone that failed to demonstrate statistically significant improvement in the primary and sec-
`ondary efficacy measures, Brief Psychiatric Rating Scale (BPRS) and PANSS, respectively for either lurasidone or
`haloperidol [50]. Thus, it is not clear if inclusion of the study in this analysis may have affected the study results.
`As more data are gathered over time, especially head-to-head randomized trials directly comparing lurasidone
`and brexpiprazole, other important differences may emerge. Although the populations of included trials were
`comparable with respect to reported patient characteristics, potential differences in other unreported baseline
`characteristics could have influenced the results reported in this analysis.
`
`Conclusion
`This network meta-analysis suggests that lurasidone has comparable efficacy to brexpiprazole along with less weight
`gain and greater reductions in total cholesterol and LDL compared with brexpiprazole. These metabolic differences
`may be important with respect to overall health outcomes. Head-to-head effectiveness studies comparing the
`relative efficacy and tolerability of lurasidone and brexpiprazole in patients with acute episodes of schizophrenia are
`warranted.
`
`Supplementary Data
`To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine
`.com/doi/f ull/10.2217/cer-2018-0016
`
`Executive summary
`
`Background
`• Schizophrenia is challenging to treat and the exact etiology remains unknown. Atypical antipsychotics are the
`treatment of choice. Although the efficacy of different atypical antipsychotics appears similar, they differ in
`tolerability most likely due to different neurological binding profiles.
`• Two of the newer treatment choices for schizophrenia were compared: lurasidone and brexpiprazole.
`• This is the first time these treatments have been compared, by using a network meta-analysis.
`Methods
`• An extensive literature search was preformed using the Preferred Reporting Items for Systematic Reviews and
`Meta-Analyses (PRISMA) approach.
`• Five lurasidone trials and three brexpiprazole trials met the inclusion criteria. A network meta-analysis compared
`the two treatments on efficacy and metabolic outcomes. For efficacy, response rate, Positive and Negative
`Syndrome Scale, and Clinical Global Impressions – Severity score were examined. Metabolic measures were
`weight change, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides.
`Results
`• The network meta-analysis found that lurasidone and brexpiprazole had similar efficacy, with the nonsignificant
`improvements in efficacy consistently favoring lurasidone.
`• Significant benefits for lurasidone on weight gain, total cholesterol and low-density lipoprotein were observed.
`Conclusion
`• Lurasidone appears to have a better metabolic profile when compared with brexpiprazole.
`• These metabolic differences may be important with respect to overall health outcomes.
`• The ability to identify significant differences may have been limited by the small number of trials available for
`inclusion in the network meta-analysis.
`
`future science group
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`www.futuremedicine.com
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`Research Article
`
`Ng-Mak, Tongbram, Ndirangu, Rajagopalan & Loebel
`
`Financial & competing interests disclosure
`D Ng-Mak, K Rajagopalan and A Loebel are employees of Sunovion Pharmaceuticals, Inc. V Tongbram and K Ndirangu are em-
`ployees of ICON Health Economics, who served as paid consultants to Sunovion Pharmaceuticals, Inc. for the development and
`publication of this study. The authors have no other relevant affiliations or financial involvement with any organization or entity
`with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those
`disclosed.
`Technical writing support was provided by MD Stensland, and GF Elphick, Agile Outcomes Research, Inc. and was funded by
`Sunovion Pharmaceuticals, Inc.
`
`Open access
`This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license,
`visit http://creativecommons.org/licenses/by-nc-nd/4.0/
`
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`Lurasidone versus brexpipraz