Skip to main content
NCBI home page
Therapeutic Advances in Psychopharmacology logoLink to Therapeutic Advances in Psychopharmacology
. 2016 Feb;6(1):39–54. doi: 10.1177/2045125315614739

Brexpiprazole: so far so good

Saibal Das 1,✉, Preeti Barnwal 2, Blessed Winston A 3, Somnath Mondal 4, Indranil Saha 5
PMCID: PMC4749739  PMID: 26913177

Abstract

This article describes the role of a newly approved antipsychotic agent brexpiprazole in the treatment of schizophrenia and major depressive disorder. This drug has high affinity for 5-HT1A, 5-HT2A, D2 and α1B,2C receptors. It displays partial agonism at 5-HT1A and D2 receptors and potent antagonism at 5-HT2A and α1B,2C adrenergic receptors. It also has some affinity (antagonism) for D3, 5-HT2B, 5-HT7 and α1A,1D receptors, and moderate affinity for H1 and low affinity for M1 receptors. These all lead to a favorable antipsychotic profile in terms of improvement of cognitive performance and sleep patterns, as well as effects on affective states and potential to treat core symptoms in schizophrenia and major depressive disorder, including cognitive deficits with a low risk of adverse effects (extrapyramidal symptoms, metabolic complications, weight gain, akathisia potential) that are commonly encountered with other typical and second-generation antipsychotic drugs. In our review, we have made an attempt to decipher the pharmacological profile of brexpiprazole from two major trials (VECTOR and BEACON). We have also tried to give a concise but detailed overview of brexpiprazole by head to head comparison of the pharmacological profile of brexpiprazole and its earlier congeners aripiprazole and prototype antipsychotic drug chlorpromazine by accessing individual summaries of product characteristics from the US Food and Drug Administration database, 2015. Relevant preclinical and clinical studies associated with this drug have been discussed with emphasis on efficacy and safety concerns. From the studies done so far, it can be concluded that brexpiprazole can be an effective monotherapy for schizophrenia and as an adjunct to other antidepressant medications in major depressive disorder.

Keywords: antipsychotic, brexpiprazole, major depressive disorder, schizophrenia

Need for another antipsychotic drug

Schizophrenia exhibits typical positive (hallucination, delusion, thought disorders) and negative (social withdrawal, lack of energy, emotion and motivation) symptoms affecting daily activities and inadvertently requires drug therapy [Lieberman et al. 2001; Bobes et al. 2007]. Cognitive deficits is a typical feature leading to both vocational and social disabilities [Coyle and Tsai, 2004; Freedman, 2003; Green et al. 2004; Niitsu et al. 2012; Sumiyoshi et al. 2001a].

The main targets in the treatment of schizophrenia are D2, 5-HT2A and α1 receptors [Bantick et al. 2001; Meltzer, 2012; Ogren et al. 2008]. Some compounds also exert their activities against 5-HT1A/6/7, α2, histamine and muscarinic receptors. The different receptor-binding profiles of current antipsychotics may contribute to variance in associated side effects as well [Correll, 2010]. The broad receptor based target effects are aimed at either improving efficacy (e.g. potential effects on affective symptoms or cognitive deficits) or mitigating adverse effects related to the central nervous system (CNS), such as extrapyramidal symptoms (EPS), or to the endocrine system, such as hyperprolactinemia [Arnt and Skarsfeldt, 1998; Roth et al. 2004; Arnt et al. 2008].

A key issue for D2 partial agonism is to determine an optimal level of intrinsic activity at the D2 receptors that would lead to a desirable stabilization of dopaminergic transmission. Too high D2 intrinsic activity leads to a lack of robust clinical activity and to adverse effects related to increased D2 receptor tonus, including nausea, vomiting, insomnia and motor effects, such as hyperkinesia and restlessness [Fleischhacker, 2005; Casey et al. 2008], whereas excessive D2 antagonist activity results in an increased risk of EPS and increased prolactin secretion [Casey, 1996]. In addition to the issue of optimal D2 intrinsic activity, actions at other receptor sites also determine clinical efficacy and tolerability of antipsychotics.

So far, the only D2 partial agonist aripiprazole, with moderate D2 intrinsic activity, has reached the market with the approved indications of schizophrenia and bipolar mania and as an add-on treatment for major depression [Fleischhacker, 2005]. Another compound (ecariprazine) with D2 intrinsic activity similar to aripiprazole is in development [Kiss et al. 2010; Citrome, 2013], but others (e.g. bifeprunox) with higher D2 intrinsic activity have seen their development discontinued [Newman-Tancredi et al. 2007] because of their insufficient clinical efficacy [De Santis et al. 2014]. At the clinically equivalent dose range leading to 80–90% D2 receptor occupancy, aripiprazole modulates a limited number of additional target receptors, the primary effect being partial agonist activity at 5-HT1A with lower potency than at D2 [Mamo et al. 2007; Dahan et al. 2009]. In addition, with aripiprazole 5-HT2A, antagonistic activity is significantly low at clinically relevant dosages [Mamo et al. 2007].

A broader target profile (e.g. on selected 5-HT receptor and α adrenoceptor subtypes) may lead to improved clinical efficacy and tolerability in the treatment of schizophrenia, including efficacy in treating positive symptoms and cognitive deficits, the main factors determining functional outcome in schizophrenia [Green, 1996]. A recent meta-analysis study suggested that 5-HT2A antagonism may reduce D2 antagonist-induced akathisia [Laoutidis and Luckhaus, 2014]. Furthermore, a broad pharmacologic profile could offer wider potential in the treatment of a variety of other CNS disorders and symptoms, such as major depressive disorder (MDD) and anxiety disorders, and post-traumatic stress disorder [Roth et al. 2004; Arnt et al. 2008; Wong et al. 2008]. It is known that D2 antagonism related side effects are minimized when combined with antagonism of 5-HT2A, a defining pharmacologic characteristic of second-generation antipsychotics [Stockmeier et al. 1993] that may be of therapeutic benefit in the treatment of schizophrenia and mood disorders [Blier and Szabo, 2005; Kuroki et al. 2008].

Selecting an antipsychotic drug requires consideration of the balance between activating and sedating adverse effects, as well as attention to EPS and cardiovascular risks [Inada et al. 2003]. New treatments that are better tolerated are needed to optimize physical health as well as social functioning [Correll et al. 2015]. Thus, there is a need for better tolerated antipsychotics with broad-based symptom control (positive and negative, as well as cognitive and behavioral) that improve patient functioning by having minimal sedating or activating effects, negligible impacts upon endocrine functioning and inconsequential neuromotor, endocrine or cardiovascular adverse effects. Brexpiprazole might offer a good option when considering these aspects [Maeda et al. 2014a].

Brexpiprazole: receptor activities and pharmacokinetics

Brexpiprazole (OPC-34712 or Lu-AF41156) is a novel molecular compound chemically and structurally similar to aripiprazole [Maeda et al. 2014a, 2014b]. On 10 July 2015, the US Food and Drug Administration (FDA) approved this drug (R&D product of Tokyo-based Otsuka Pharmaceutical Company Ltd) to treat adults with schizophrenia and as an add-on treatment to an antidepressant medication to treat adults with MDD based on 1310 participants in two 6-week pivotal trials (VECTOR and BEACON) [US FDA News Release, 2015].

The major human and rat receptor affinities (Ki) with functional activities of brexpiprazole are presented in Table 1. These receptor properties are thought to be related to the drug’s putative antipsychotic and antidepressant effects.

Table 1.

Major human and rat receptor affinities (Ki) with functional activities of brexpiprazole [Maeda et al. 2014b].

Receptors Ki values in human Ki values in rats Functional activities
5-HT1A 0.12 nM 0.09 nM Partial agonism
5-HT2A 0.47 nM 3.8 nM Potent antagonism
5-HT2B 1.9 nM Antagonism
D2L 0.3 nM 0.35 nM Partial agonism
D3 1.1 nM Antagonism
α1B 0.17 nM 18 nM Potent antagonism
α2C 0.59 nM Potent antagonism
H1 19 nM Antagonism
Open in a new tab

Partial D2 receptor agonism is thought to have a buffering action on dopamine neurotransmission by stimulating D2 receptors under low dopamine conditions, while dampening their activation when dopamine levels are high [Burris et al. 2002]. 5-HT1A improves certain types of memory function, as well as cognitive performance in patients with schizophrenia [Sumiyoshi et al. 2001a, 2001b]. Also, antagonism of α adrenergic receptors is a pharmacologic feature that may have therapeutic implications for schizophrenia and depression [Fawcett and Barkin, 1998; Arnsten, 2004; Marcus et al. 2010]. As per a recent review, α2A,2C are also targets for acute psychotic disorders [Brosda et al. 2014]. This drug has been tested in clinical trials evaluating the treatment of schizophrenia, agitation associated with Alzheimer’s disease and as an adjunct treatment of post-traumatic stress disorder and MDD [Citrome, 2013].

Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the D2 receptor, stronger antagonism at 5-HT2A and stronger affinity for nor-epinephrine transporter [Maeda et al. 2014a]. As a result, it has lower potential to induce D2 partial agonist mediated adverse effects (akathisia, insomnia, restlessness, nausea) [Fleischhacker, 2005]. The potential to induce D2 antagonist-like adverse effects (EPS, hyperprolactinemia and possibly tardive dyskinesia) is also considered to be lower than with silent D2 receptor antagonists. Further, brexpiprazole’s balanced 5-HT2A/D2 and 5-HT1A/D2 receptor binding profile may contribute to low incidences of both activating and neuromotor adverse effects clinically. Finally, brexpiprazole has a moderate affinity for histamine H1 receptors, which may result in low sedation levels as well as weight gain [Maeda et al. 2014a, 2014b; Kroeze et al. 2003].

Despite a different action on D2 autoreceptors, brexpiprazole improves behavioral measures predictive of antipsychotic efficacy, like apomorphine-induced stereotypy and the conditioned avoidance response [Maeda et al. 2014a]. Also, in light of the N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia [Hashimoto, 2006, 2014; Hashimoto et al. 2013], brexpiprazole was shown to improve the NMDA receptor antagonist phencyclidine-induced cognitive deficits in the novel object recognition test in rodents [Maeda et al. 2014b; Hashimoto et al. 2005; Yoshimi et al. 2014].

Brexpiprazole is metabolized primarily by the cytochrome P450 3A4 (CYP3A4) and 2D6 enzymes. Hence, there is a possibility of drug–drug interactions with drugs that inhibit or induce CYP3A4 (like aripiprazole, quetiapine, fluvoxamine, venlafaxine, citalopram, mirtazapine, etc.) and CYP2D6 (like aripiprazole, risperidone, haloperidol, clozapine, iloperidone, doxepin, etc.) activity. It has a long half life of more than 72 h. Brexpiprazole also does not have any active metabolites. Drug absorption, metabolism and excretion are not significantly affected by age, sex, renal impairment or liver impairment, and therefore, dose adjustments are not likely to be necessary based on these factors [Howland, 2015]

Preclinical insights

In vivo studies in rats demonstrated that in the dorsal raphe nucleus, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism and was more potent than aripiprazole. In the locus coeruleus, it reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2, 5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing demonstrating 5-HT2A antagonistic action in rats. It also reversed the inhibitory effect of the dopamine agonist apomorphine on ventral tegmental area dopaminergic neurons demonstrating partial agonistic action on D2 receptors. Brexpiprazole had no effect on extracellular levels of serotonin or noradrenaline in prefrontal cortex and ventral hippocampus in rats. High doses of brexpiprazole increased extracellular levels of histamine in the prefrontal cortex. This may be a consequence of its moderate affinity and antagonist activity on H1 receptors, as shown in vitro [Maeda et al. 2014a].

Compared with aripiprazole, which significantly inhibited the firing activity of ventral tegmental area dopaminergic neurons, brexpiprazole displayed lesser activity at D2 receptors. In vivo, it acts neither as a pure antagonist nor as an agonist with high intrinsic activity on D2 autoreceptors. The difference in effects on dopamine neurons of aripiprazole and brexpiprazole is likely due to a lower intrinsic activity of the latter agent at D2 receptors, in line with their in vitro profiles [Maeda et al. 2014b]. In the rat hippocampus, brexpiprazole acts as a full agonist at 5-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α2 adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. The in vivo agonism of brexpiprazole on 5-HT1A receptors is also more potent than aripiprazole without affecting terminal 5-HT1B autoreceptor activity as shown in rats [Oosterhof et al. 2014].

Brexpiprazole acts as a potent α2 adrenergic heteroceptor antagonist like mianserin and mirtazapine [Mongeau et al. 1993; Haddjeri et al. 1996]. In the lateral geniculate nucleus, it displays α1B adrenergic receptor antagonistic action. Other studies also suggest antagonistic properties of brexpiprazole predominantly at α1B adrenergic receptors, consistent with its 20-fold higher affinity for this receptor subtype over α1A and α1D [Maeda et al. 2014b]. In the rat hippocampus, there was no action on postsynaptic α2 adrenergic receptors and the norepinephrine transporter. Acute brexpiprazole administration reduced inhibition of two important interaction nodes between the 5-HT and norepinephrine systems in rats. First, it blocked 5-HT2A receptors and also it blocked α2 adrenergic receptors on 5-HT terminals [Oosterhof et al. 2014].

Brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. It also has inhibitory activity in a drug-induced hyperactivity model. The effects in the cognitive tests are superior to those of aripiprazole [Maeda et al. 2014b]. The potency of brexpiprazole to induce antipsychotic-like activity is in the same range as that predicting in vivo D2 receptor occupancy [Maeda et al. 2014b]; cataleptogenic activity is only induced at high dosages likely due to D2 partial agonism and its 5-HTergic activities [Kikuchi et al. 1995; Meltzer 1999]. Similar to aripiprazole, brexpiprazole has low potential to induce EPS at relevant clinical exposures, leading to 60–90% D2 receptor occupancy [Yokoi et al. 2002]. Brexpiprazole showed partial agonist activity at D2 and D3 receptors, even in cloned cell assays with much lower intrinsic activity than aripiprazole. Moreover, the potent inhibition by brexpiprazole of the apomorphine-induced eye blinking in monkeys is consistent with a low intrinsic activity at D2 receptors [Kleven and Koek, 1996]. A combined 5-HT1A agonism and 5-HT2A antagonism is a likely mechanism in attentional set-shifting tests with brexpiprazole [Maeda et al. 2014a].

Subchronic oral administration of brexpiprazole significantly attenuated NMDA receptor antagonist, phencyclidine-induced cognitive deficits in mice in a dose-dependent manner and this was significantly antagonized by coadministration of selective 5-HT1A receptor antagonist WAY-100,635. It was reported earlier that repeated dosing with PCP significantly reduced the density of 5-HT1A receptors in mouse hippocampus, although the precise mechanisms underlying this action are currently unknown [Hagiwara et al. 2008]. These findings suggest that brexpiprazole can ameliorate PCP-induced cognitive deficits in mice via 5-HT1A receptors. Therefore, brexpiprazole could ameliorate cognitive deficits as seen in schizophrenia and other neuropsychiatric diseases as well [Yoshimi et al. 2015].

Some in vitro studies suggest that selective D2 antagonists alone may not have any effects, but D2 antagonism in conjunction with 5-HT2A antagonism or 5-HT1A partial agonism may increase extracellular dopamine and acetylcholine [Mørk et al. 2009; Meltzer, 1999, 2012]. Another preclinical study showed that brexpiprazole significantly ameliorated dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior and had no effect on social recognition or exploratory behaviors in untreated control mice. By contrast, neither risperidone nor olanzapine altered dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced social recognition deficits again via 5-HT1A receptor activation. It is possible that 5-HT1B receptor may, in part, be involved in the mechanisms of action of brexpiprazole on social recognition deficits [Yoshimi et al. 2015].

Another study has shown that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC 12 cells, in a concentration-dependent manner mediated through 5-HT1A and 5-HT2A receptor antagonism, and subsequent Ca2+ signaling via IP3 receptors [Ishima et al. 2015]. Considering the function of the aforementioned signaling molecules in regulating protein synthesis dependent learning and memory [Costa-Mattioli et al. 2009], brexpiprazole-driven changes in these pathways may promote synthesis of new proteins associated with neurite outgrowth. It was previously reported that fluoxetine, but not paroxetine, significantly potentiated neurite outgrowth report [Nishimura et al. 2008]. The IP3 receptors promote NGF-induced neurite outgrowth in PC 12 cells [Nishimura et al. 2008; Ishima et al. 2008, 2012; Minase et al. 2010; Hashimoto and Ishima, 2010, 2011; Itoh et al. 2011]. Recently, it was also concluded that aripiprazole could potentiate NGF-induced neurite outgrowth in PC 12 cells, most likely through interaction with 5-HT1A receptors [Ishima and Hashimoto, 2012a; Ishima et al. 2012]. Heat shock protein (HSP) 90α is being differentially expressed between control PC 12 cells treated with NGF and those treated with NGF and aripiprazole [Ishima et al. 2012]. Brexpiprazole therapy also increased HSP 90α protein levels, which potentiated NGF-induced neurite outgrowth. Thus, it would appear that activation of 5-HT1A receptors as well as blockage of 5-HT2A receptors is an integral part of the mechanisms that drive brexpiprazole enhancement of NGF-induced neurite outgrowth. Interestingly, it was also found that brexpiprazole could potentiate the effects of fluoxetine (or paroxetine) on neurite outgrowth. Since brexpiprazole has been used as add-on therapy of the current antidepressant therapy, the potentiating effect of brexpiprazole on neurite outgrowth is of great interest [Ishima et al. 2015].

Relevant clinical trials

The VECTOR trial

In the VECTOR trial [ClinicalTrials.gov identifier: NCT01396421], the efficacy, safety and tolerability of brexpiprazole and placebo were compared in adults with acute schizophrenia [Correll et al. 2015]. This was a 6-week, multicenter (65 global centers), randomized, double-blind, placebo-controlled study. Eligible patients were 18–65 years old, had a DSM IV TR diagnosis of schizophrenia confirmed by the Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders Studies, experienced an acute exacerbation, and would benefit from hospitalization or continued hospitalization for treatment.

Patients were randomly assigned to daily brexpiprazole at a dosage of 0.25, 2 or 4 mg, or placebo (1:2:2:2) for 6 weeks. There was a 14-day screening phase, a 6-week double-blind treatment phase and a 30-day follow-up phase. Efficacy was assessed by using the Positive and Negative Syndrome Scale (PANSS) [Kay et al. 1999], the Clinical Global Impressions Scale (CGI) severity of illness and improvement scales [Guy, 1976], and the Personal and Social Performance scale [Gharabawi et al. 2007; Morosini et al. 2000]. The primary efficacy measure was change from baseline at week 6 in PANSS total score. Secondary efficacy measures were change from baseline at weeks 1–5 in PANSS total score; change from baseline at week 6 in the CGI severity rating (key secondary endpoint measure), Personal and Social Perfor-mance score, and PANSS positive and negative symptom subscale scores; CGI improvement rating at week 6; rate of response at week 6 (defined as change from baseline by 30% in PANSS total score or CGI improvement score of 1 or 2); discontinuation rate due to lack of efficacy; and change from baseline at week 6 in PANSS score on the excited component (comprising excitement, hostility, tension, uncooperativeness, and poor impulse control scores) [Montoya et al. 2011] and in scores on the five PANSS factors [Marder et al. 1997].

At week 6, compared with placebo, brexpiprazole at 2 and 4 mg produced statistically significantly greater reductions in PANSS total score and CGI severity score (p = 0.0001)and its effects on the key secondary efficacy endpoint measure was also statistically significant compared with placebo (p = 0.0006). Statistically significant improvement was seen in these two brexpiprazole groups within 1–2 weeks of initiating treatment and was maintained throughout the treatment period. Brexpiprazole at dosages of 2 and 4 mg demonstrated efficacy in treating both positive and negative symptoms of schizophrenia, and they reduced agitation as measured by the PANSS excited component. Rates of response (30% improvement in PANSS total score or CGI improvement rating of 1 or 2) were higher with the 2 and 4 mg brexpiprazole dosages than with placebo (p = 0.0004 and p = 0.004, respectively). The 0.25 mg dosage however did not have any clinically relevant effects on any of the efficacy measures. The 2 and 4 mg dosages demonstrated efficacy in four of five PANSS dimensions [Marder et al. 1997], positive symptoms, negative symptoms, disorganized thought and uncontrolled hostility/excitement.

The limitations of the studies were lack of an active comparator, short study duration and inclusion of patients with schizophrenia without other psychiatric comorbidities. These data show that brexpiprazole can also be used as adjunctive treatment in patients with MDD and inadequate responding to antidepressants. Phase II and III studies have actually indicated that adjunctive brexpiprazole is effective and well tolerated in this population [Thase et al. 2014, 2015a, 2015b].

The BEACON trial

The objective of the BEACON trial [ClinicalTrials.gov identifier: NCT01393613] was to evaluate the efficacy, safety and tolerability of brexpiprazole versus placebo in adults with acute schizophrenia [Kane et al. 2015]. This was a 6-week, multicenter (64 global centers), randomized, double-blind, placebo-controlled double-blind phase III study. Eligible subjects were 18–65 years of age with a current diagnosis of schizophrenia (defined by DSM IV TR and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders Studies) who were experiencing an acute exacerbation of psychotic symptoms and marked deterioration of usual function, as demonstrated by meeting all of the following criteria at screening and baseline visits: Total Brief Psychiatric Rating Scale (BPRS) score of at least 40; score of at least 4 on two or more BPRS items (hallucinatory behavior, unusual thought content, conceptual disorganization or suspiciousness); and CGI-S score of at least 4.

Patients with acute schizophrenia were randomized to brexpiprazole 1, 2 or 4 mg, or placebo (2:3:3:3) once daily. There was a pretreatment screening phase of up to 14 days, a 6-week double-blind treatment period and a 30-day follow-up phase. The primary endpoint was changed from baseline at week 6 in PANSS total score [Kay et al. 1999] and the key secondary endpoint was CGI severity score [Guy, 1976] at week 6. Additional secondary outcomes were changes from baseline at week 6 in Personal and Social Performance scale [Morosini et al. 2000; Gharabawi et al. 2007], PANSS positive and negative subscales [Kay et al. 1999], PANSS excited component [Montoya et al. 2011] and Marder Factor [Lindenmayer et al. 1995; Von Knorring and Lindstrom, 1995; Marder et al. 1997; Nakaya et al. 1999; Van der Gaag et al. 2006] scores, CGI Improvement score at week 6, response rate and discontinuation rate for lack of efficacy. Response was defined as mean reduction from baseline in PANSS total score of at least 30%, or CGI Improvement score of 1 (very much improved) or 2 (much improved) at week 6.

Brexpiprazole 4 mg showed statistically significant improvement versus placebo for primary (p = 0.0022), secondary (p = 0.0015) endpoints and on multiple secondary efficacy outcomes. Brexpiprazole 1 and 2 mg also showed numerical improvements versus placebo, although not statistically significant. There were also improvements over placebo in Personal and Social Performance scale, PANSS positive subscale, PANSS negative subscale, CGI Improvement response rate, PANSS excited component and PANSS Marder Factor scores. The results obtained confirmed that of the three doses tested, brexpiprazole 4 mg was the optimal effective dose in this study. The placebo response in this study was slightly higher for the primary endpoint compared with the placebo response obtained in the VECTOR trial; the high placebo response might have obscured true brexpiprazole versus placebo treatment differences within this study.

The limitations of the study were the lack of an active comparator and relatively short duration. In conclusion, brexpiprazole 4 mg is an efficacious and well tolerated agent treatment for acute schizophrenia in adults.

Other trials

The FDA also accepted a concurrent new drug application (NDA) submission to review a proposed indication for adjunctive treatment of MDD (using brexpiprazole together with an antidepressant drug). The NDA for MDD was supported by efficacy and safety data from two phase II studies [ClinicalTrials.gov identifier: NCT00797966, NCT01052077] and two other pivotal phase III studies [ClinicalTrials.gov identifier: NCT01360645, NCT01360632] [Howland, 2015]. The design of the two phase III studies was similar, but each study investigated different brexpiprazole doses [Thase et al. 2014, 2015a, 2015b]. The PYXIS trial [ClinicalTrials.gov identifier: NCT01360645] was the first pivotal study demonstrating superior efficacy of brexpiprazole 2 mg per day over placebo in 379 individuals with MDD [Thase et al. 2014, 2015a, 2015b]. The POLARIS trial [ClinicalTrials.gov identifier: NCT01360632] was the second pivotal study, which demonstrated that brexpiprazole 1 and 3 mg per day were significantly more effective than placebo in 677 individuals with MDD [Thase et al. 2014, 2015a, 2015b].

On the ClinicalTrials.gov website, 41 ongoing or completed clinical studies (phase I, II or III) are listed for brexpiprazole or OPC-34712. In addition to the studies described above as part of the NDA submissions, 27 other studies are listed for schizophrenia or MDD. Additional clinical trials include a completed phase II study in attention-deficit/hyperactivity disorder [ClinicalTrials.gov identifier: NCT01074294], an ongoing phase III study in post-traumatic stress disorder [ClinicalTrials.gov identifier: NCT01987960] and three ongoing phase III studies for agitation associated with dementia of the Alzheimer’s type [ClinicalTrials.gov identifier: NCT01862640, NCT01922258, NCT02192554]. The results from completed trials have not been published or posted on ClinicalTrials.gov. The breadth of studies investigating the use of brexpiprazole is impressive, a reflection of the novel pharmacological properties of this drug [Howland, 2015].

Safety concerns

The VECTOR trial

Safety and tolerability variables were adverse events, bodyweight, laboratory measurements, vital signs, electrocardiogram, Barnes Akathisia Rating Scale [Barnes, 1989], Simpson Angus Scale [Simpson and Angus, 1970], Abnormal Involuntary Movement Scale, and Columbia-Suicide Severity Rating Scale [Posner et al. 2011; Chappell et al. 2012]. The overall incidence of treatment-emergent adverse events was lower in the three brexpiprazole groups than placebo. The same was true for discontinuation due to adverse events. Akathisia was more frequently reported in the 2 and 4 mg brexpiprazole groups and mostly during the first 3 weeks of treatment. The incidences of other activating (restlessness, insomnia, anxiety) and sedating (somnolence, fatigue, sedation) treatment-emergent adverse events in patients receiving brexpiprazole were similar to or lower than the rates in patients receiving placebo. The most frequently reported serious adverse events in all treatment groups were psychiatric disorders (schizophrenia, psychotic disorder). There were no deaths during the study. Increased body weight was reported as a treatment-emergent adverse event in patients who received 2 and 4 mg of brexpiprazole. Slight increases occurred in total cholesterol and high-density lipoprotein cholesterol from baseline to the last visit for 2 and 4 mg of brexpiprazole compared with slight decreases in the placebo group, but these changes were neither clinically relevant nor statistically significant. There were slight increases in low-density lipoprotein cholesterol and triglycerides in the 4 mg brexpiprazole group, but these differences were also not clinically relevant. All four groups had minimal increases in glucose. Shifts to abnormal fasting lipid or glucose values were similar in the brexpiprazole and placebo groups. Metabolic related treatment-emergent adverse events were reported by three brexpiprazole patients: diabetes mellitus (0.25 mg), hypertriglyceridemia (4 mg) and increased glycosylated hemoglobin level. Mean prolactin concentrations increased from baseline to the last visit in both female and male patients in the 4 mg brexpiprazole group, while reductions were seen in the 2  mg brexpiprazole and placebo group. Hyperprolactinemia was reported as a treatment-emergent adverse event for one patient in the 2 mg brexpiprazole group. The mean changes in QT interval from baseline to the last visit, as corrected by Bazett’s formula, was also not significant compared with placebo. The occurrence of suicidal ideation or behavior, as recorded on the Columbia-Suicide Severity Rating Scale, was low. Notably, more patients randomly assigned to placebo than brexpiprazole discontinued the study because of lack of efficacy or adverse events.

The BEACON trial

Safety variables examined during this clinical trial included adverse events, physical examinations, vital signs, body weight, laboratory measurements including hematology, serum chemistry (including prolactin), urinalysis and pregnancy tests, vital signs, electrocardiograms and EPS evaluation using the Simpson Angus Scale [Simpson and Angus, 1970], Abnormal Involuntary Movement Scale [Guy, 1976] and the Barnes Akathisia Rating Scale [Barnes, 1989]. The Columbia-Suicide Severity Rating Scale [Posner et al. 2011; Chappell et al. 2012] was used to assess and classify reported suicidal behavior. In this trial, 58.6% patients reported at least one treatment-emergent adverse event. No events met the criteria for common adverse events (defined as ⩾5% in brexpiprazole treatment groups and at least two times the placebo rate). Fewer patients in the brexpiprazole treatment groups discontinued treatment due to psychiatric treatment-emergent adverse events than placebo patients. In all treatment groups, the most frequently reported serious treatment-emergent adverse events and discontinuations due to treatment-emergent adverse events were indicative of the underlying condition of schizophrenia.

The most common treatment-emergent adverse events were headache, insomnia and agitation; incidences of akathisia were lower in the brexpiprazole treatment groups versus placebo. Brexpiprazole treatment was associated with moderate weight gain at week 6 and there were no clinically relevant changes in laboratory parameters and vital signs. Changes in laboratory measurements, vital signs or electrocardiograms did not show any consistent differences between the brexpiprazole and placebo treatment groups. Small mean decreases in prolactin levels were seen in all treatment groups with the exception of women treated with brexpiprazole 2 mg. Incidences of potentially clinically relevant prolactin values were highest in the brexpiprazole 4 mg group. Potentially clinically relevant changes in creatine phosphokinase levels were similar across all brexpiprazole groups and higher than the placebo group. As for blood glucose levels, there was a very small mean decrease in brexpiprazole 1 and 2 mg groups and a very small mean increase was observed in the brexpiprazole 4 mg group. Incidences of potentially clinically relevant triglyceride values were slightly greater in the brexpiprazole 4 mg group. No clinically meaningful changes in electrocardiograms were reported, and the number of patients with new-onset QTc elevation was low across all treatment groups.

Other safety reports and issues

Other reported side effects include headache, dizziness, insomnia, somnolence, nausea, anxiety, fatigue and mild weight gain. Weight gain is comparable to that seen with aripiprazole, which is not surprising given their pharmacological similarity, but is less than that observed for other atypical antipsychotic drugs. A meta-analysis of second-generation antipsychotics has suggested that there are differences between agents in their ability to induce EPS [Rummel-Kluge et al. 2012], although only aripiprazole was reported to have a relatively low risk [Leucht et al. 2013]. A moderate increase in body weight with brexpiprazole was noted, but there was no evidence of statistically significant or clinically relevant adverse effects on metabolic measures and prolactin when compared with those for placebo. This finding is important given that metabolic side effects are a serious concern with some second-generation antipsychotics, namely clozapine, olanzapine, quetiapine [De Hert et al. 2012; Rummel-Kluge et al. 2012; Correll et al. 2014] or lurasidone [Leucht et al. 2013]. Interestingly, brexpiprazole resulted in numerically fewer QTc changes than placebo when the QTc interval is corrected by using Bazett’s formula. Overall, the tolerability profile of brexpiprazole appears to be consistent with its pharmacological profile, whereby it shows a balanced 5-HT2A and 5-HT1A receptor binding affinity relative to D2, with less intrinsic activity at the D2 receptor than aripiprazole and moderately low affinity for receptors that have been associated with sedation and weight gain [Maeda et al. 2014b]. Elevations of serum creatine phosphokinase have been observed with other atypical antipsychotics, such as the D2 antagonists clozapine and olanzapine and the partial D2 agonist aripiprazole [Melkersson, 2006; Potkin et al. 2013; Laoutidis and Kioulos, 2014]. Brexpiprazole may be associated with dose-dependent orthostatic hypotension (possibly related to α1 adrenergic receptor antagonism). The drug has no significant effects on histamine receptors (associated with sedation and weight gain) or cholinergic receptors (associated with impaired cognitive function) (Table 2) [Howland, 2015].

Table 2.

Notable adverse effects of brexpiprazole revealed from clinical trials.

Trials Adverse effects
VECTOR trial Schizophrenia, psychotic disorder, akathisia, slight increases occurred in total cholesterol, LDL cholesterol, triglyceride, diabetes mellitus, hyperprolactinemia
BEACON trial Headache, insomnia, agitation, weight gain, rise in creatine phosphokinase, hypertriglyceridemia
Other trials Headache, dizziness, insomnia, somnolence, nausea, anxiety, fatigue, weight gain, elevations of serum creatine phosphokinase, orthostatic hypotension
Open in a new tab

LDL, low-density lipoprotein.

A placebo-controlled phase I study in older adults (aged 70–85) with MDD was completed [ClinicalTrials.gov identifier: NCT01670279], but a phase III study [ClinicalTrials.gov identifier: NCT01837797] in a similar population was terminated apparently because of poor recruitment rather than for safety reasons [Howland, 2015]. Although brexpiprazole has been investigated for a variety of potential therapeutic uses in psychiatry, one notable exception is the lack of studies proposed or conducted for the treatment of bipolar depression or mania. How brexpiprazole compares with other antipsychotic drugs will be important to evaluate in head to head studies. A randomized study comparing brexpiprazole and aripiprazole in schizophrenia has been recently completed [ClinicalTrials.gov identifier: NCT02054702]. In addition, placebo-controlled studies comparing brexpiprazole and quetiapine have been completed (in schizophrenia) [ClinicalTrials.gov identifier: NCT01810380] and are also ongoing (as adjunctive treatments for MDD) [ClinicalTrials.gov identifier: NCT01727726] [Howland, 2015].

However, brexpiprazole has not been studied in children or adolescents. The FDA has issued a boxed warning indicating increased risk of death associated with the off-label use of these drugs (brexpiprazole) to treat behavioral problems in older people with dementia-related psychosis, increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants [US FDA News Release, 2015].

A comparison

This article is not an exhaustive review of the literature on brexpiprazole or the impact of brexpiprazole on patient outcomes, but rather considers selected publications to direct readers to emerging evidence and provide some context for the later discussion about brexpiprazole in the arena of antipsychotic therapy. Further, well explored systematic reviews on brexpiprazole have been published by other groups which the readers may want to consider for their insight on brexpiprazole. Goff has given an interesting precise account on brexpiprazole mainly by comparing the results of various trial-related data [Goff, 2015]. However, Citrome has given an elaborate explanation of brexpiprazole by extracting data from around 17 pivotal registration trials on brexpiprazole, including poster abstracts and product labeling [Citrome, 2015]]. It is very exploratory but exhaustive. In our review, we have made an attempt to decipher the pharmacological profile of brexpiprazole from two major trials (VECTOR and BEACON). We have also tried to give a concise but detailed overview of brexpiprazole by head to head comparison of the pharmacological profile of brexpiprazole with its earlier congeners aripiprazole and prototype antipsychotic drug chlorpromazine by accessing individual summaries of product characteristics from the FDA database [FDA, 2015] and authentic literature presented in the references (Table 3). We hope our approach will definitely enrich readers’ insight on the antipsychotic properties of brexpiprazole.

Table 3.

Head to head pharmacological comparison of brexiprazole with aripiprazole and prototype typical first-generation antipsychotic drug chlorpromazine (US-FDA Database, 2015).

Points of comparison Brexiprazole Aripiprazole Chlorpromazine
Therapeutic class Second-generation antipsychotic First-generation antipsychotic
Chemical class Dihydrocarbostyril Phenothiazine
Pharmacodynamic aspects and principles of modes of action for psychosis at receptor level Serotonin–dopamine activity modulator (‘Goldilocks-like’ drugs):
  D2 partial agonist
  5-HT1A partial agonist
  5-HT2A antagonist
Optimize dopaminergic neurotransmission in between mesolimbic and mesocortical pathway which would in turn reduce positive and negative symptoms of schizophrenia respectively
Preclinical insights demonstrated potent 5-HT1A agonism of brexiprazole over aripiprazole and both less affinity and intrinsic activity on D2 receptor
Fewer incidences of both D2-agonist and D2-antagonist mediated adverse effects like akathisia, insomnia, restlessness, nausea and EPS, hyperprolactinemia and tardive dyskinesia respectively compared with aripiprazole		 Mesolimbic dopaminergic tract
Decrease in positive symptoms
Mesocortical dopaminergic tract
Worsening of negative symptoms:
  D2 receptor antagonist
  5-HT2A receptor antagonist
Along with above actions it also imparts potent antagonistic effects on muscarinic, histaminic and adrenergic receptors, and resulted in high incidence of adverse effects mediated by these receptor antagonists
Incidence of EPS Reported incidence rate was less than aripiprazole Mild and transient and respond to dose reduction Pronounced, often resulted in dose withdrawal
Pharmacokinetic aspects Tmax: oral 4 h
95% bioavailability
Highly plasma protein bound (>99%)
Steady state plasma concentrations 10–12 days
Not affected by hepatic or renal impairment
Metabolized in liver, mainly by CYP3A4 and CYP2D6
Inactive metabolite (DM-3411)
Plasma t1/2: parent drug: 91 h
Excretion: feces (<14%) and urine (<1%)		 Tmax: oral: 3–5 h, intramuscularly 1–3 h
87% bioavailability
Highly plasma protein bound (>99%)
Steady state plasma concentrations by 14 days
Not affected by hepatic or renal impairment
Metabolized in liver, mainly by CYP3A4 and CYP2D6
Active metabolite (dehydroARI)
Plasma t1/2: parent drug: 75 h, metabolite: 94 h
Excretion: feces (55%) and urine (25%)		 Tmax: oral: 1–4 h, intramuscularly 6–24 h
10–80% bioavailability
Highly plasma protein bound (~90–99%)
Steady state plasma concentrations: variable
Hepatic or renal impairment: unpredictable
Metabolized in gut wall, lung and liver, mainly by cytochrome P450 microsomal pathways CYP2D6, CYP1A2 mediated into over 10 major metabolites (very unpredictable as >150 metabolites formed with variable effects)
Plasma t1/2:parent drug: 2–60 h
Excretion: feces (5–6%) and urine (20–70%)
Minimum effective therapeutic dose 2 mg 10 mg 100 mg
Dosage forms Oral Oral and intramuscular Oral, intramuscular, rectal
FDA approved indications spectrum and age Schizophrenia and as an adjunct in treatment-resistant depression in adults
Short spectrum limited to adults)		 Schizophrenia: adults and adolescents
Manic and mixed episodes associated with bipolar I disorder: adults and adolescents
Adjunctive treatment of major depressive disorder
Irritability associated with autistic disorder (6–17 years)
Treatment of Tourette’s disorder
Intermediate spectrum of activity		 Wide spectrum of antipsychotic activity
Used in adults, children
Cost Matter of concern Generic Generic
Commonly observed adverse reaction profiles (incidence ⩾ 5%) Weight increased and akathisia
Based on few clinical trial data
As time progresses, list of reported ADRs expected to increase		 Akathisia, EPS, somnolence, sedation, restlessness, tremor, insomnia, fatigue, nausea, blurred vision, salivary hyper secretion, vomiting, pyrexia, drooling, decreased appetite, lethargy and constipation
As time progresses, list of reported ADRs expected to increase
Growing number of case reports of metabolic complications is the area of concern		 Infrequent hence unpredictable: EPS, akathisia, dystonia, muscle stiffness, neuroleptic malignant syndrome, Parkinsonism, tardive dyskinesia
Common: anticholinergic effects, sedation, weight gain, erectile dysfunction,
oligomenorrhea or amenorrhea
Less common: cerebral edema, orthostatic hypotension (after intramuscular injection), tachycardia, agitation, anxiety, depression, dizziness, euphoria, headache, insomnia, poikilothermia, restlessness, weakness, anorexia, constipation, dyspepsia, ileus, lens opacities (prolonged use)
Uncommon: ECG changes, photosensitivity, pruritus, galactorrhea, ejaculatory disorder, diarrhea, blood dyscrasia
Rare: seizure, priapism, cholestatic jaundice
The actual incidence rate may vary depending on disease condition, management strategy, age of the patient under treatment
Pregnancy category Yet to assign Category C Category N
FDA boxed warning Increased mortality in elderly patients with dementia-related psychosis and suicidality under other antidepressant drugs Increased mortality in elderly patients with dementia-related psychosis
Contraindications Known hypersensitivity Known hypersensitivity Known hypersensitivity to phenothiazine
Comatose states or in the presence of large amounts of CNS depressants (alcohol, barbiturates, narcotics, etc.)
Dosage adjustment during concomitant administration with other drugs by affecting key metabolizing enzymes As both the drugs metabolized by CYP3A4 and CYP2D6, similar outcomes are expected hence dosage adjustment is recommended Multiple metabolic enzymes, multiple metabolites having the potential to interact with large number of pharmacological agents
A huge drug–drug interaction profile is available for this drug
Among these drug interactions, some might be life threatening
Factors Dosage adjustments
Strong CYP2D6 (SSRI) or CYP3A4 (e.g. ketoconazole, ritonavir etc.) inhibitors Administer half (50%) of usual dose
Strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors Administer a quarter (25%) of usual dose
Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors Administer a quarter (25%) of usual dose
Strong CYP3A4 inducers (e.g. carbamazpine) Double the usual dose and further adjust based on clinical response
Open in a new tab

ADR, adverse drug reaction; CNS, central nervous system; CYP, cytochrome P450; D, dopamine; ECG, electrocardiogram; EPS, extrapyramidal symptoms; FDA, US Food and Drug Administration; HT, hydroxytryptamine; SSRI, selective serotonin reuptake inhibitor; Tmax, time to reach maximum concentration in blood; t1/2, half life.

Conclusion

The above discussion gives an insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia [Oosterhof et al. 2014]. As the therapeutic effect of potent 5-HT2A receptor antagonism in combination with 5-HT reuptake inhibitors is well recognized [Nelson and Papakostas, 2009], the present data support the use of brexpiprazole as an augmentation strategy. Its target optimization included D2 partial agonism with low intrinsic activity, 5-HT1A partial agonism and antagonism at 5-HT2A, α1B,2C adrenergic receptors [Maeda et al. 2014a], supporting a favorable antipsychotic profile with low EPS risk and potential to treat core symptoms in schizophrenia, including cognitive deficits [Arnt and Skarsfeldt, 1998; Drouin et al. 2002; Marcus et al. 2010; Newman-Tancredi and Kleven, 2011; Sallinen et al. 2013].

The fact that the antagonist activity at 5-HT2A and activity at D2 receptors occurred at similar doses of brexpiprazole, whereas aripiprazole had a lower 5-HT2A receptor occupancy at any given D2 receptor occupancy, may lead to clinical advantages, as 5-HT2A antagonism is thought to contribute to antipsychotic activity, reduced akathisia potential, improvement of cognitive performance and sleep patterns, as well as effects on affective states [Monti, 2010; Snigdha et al. 2010; Ebdrup et al. 2011; Laoutidis and Luckhaus, 2014]. The effects of brexpiprazole on HT1A and D3 receptors are important for their pharmacological profiles. Partial agonism at HT1A and D3 receptors is involved in the antipsychotic and procognitive profiles as well as effects on affective states [Newman-Tancredi and Kleven, 2011; Gross and Drescher, 2012].

Thus, from all the preclinical and clinical studies conducted so far, it can be aptly concluded that brexpiprazole can be used as monotherapy in schizophrenia and as an adjunct to antidepressant medication in MDD.

Acknowledgments

The authors acknowledge Dr Jacob Peedicayil, Professor, Department of Pharmacology, Christian Medical College, Vellore, India for giving valuable suggestions in manuscript preparation.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare that there is no conflict of interest.

Contributor Information

Saibal Das, Department of Pharmacology, Christian Medical College, Vellore, 632002, India.

Preeti Barnwal, Jamia Hamdard (Hamdard University), New Delhi, India.

Blessed Winston A, Christian Medical College, Vellore, India.

Somnath Mondal, Calcutta School of Tropical Medicine, Kolkata, India.

Indranil Saha, Medical College Kolkata, Kolkata, India.

References

  1. Arnsten A. (2004) Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berl) 174: 25–31. [DOI] [PubMed] [Google Scholar]
  2. Arnt J., Bang-Andersen B., Dias R., Bøgesø K. (2008) Strategies for pharmacotherapy of schizophrenia. Drugs Future 33: 777–791. [Google Scholar]
  3. Arnt J., Skarsfeldt T. (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18: 63–101. [DOI] [PubMed] [Google Scholar]
  4. Bantick R., Deakin J., Grasby P. (2001) The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol 15: 37–46. [DOI] [PubMed] [Google Scholar]
  5. Barnes T. (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154: 672–676. [DOI] [PubMed] [Google Scholar]
  6. Blier P., Szabo S. (2005) Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 66(Suppl. 8): 30–40. [PubMed] [Google Scholar]
  7. Bobes J., Garcia-Portilla M., Bascaran M., Saiz P., Bousono M. (2007) Quality of life in schizophrenic patients. Dialogues Clin Neurosci 9: 215–226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brosda J., Jantschak F., Pertz H. (2014) α2-adrenoceptors are targets for antipsychotic drugs. Psychopharmacology 231: 801–812. [DOI] [PubMed] [Google Scholar]
  9. Burris K., Molski T., Xu C., Ryan E., Tottori K., Kikuchi T., et al. (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302: 381–389. [DOI] [PubMed] [Google Scholar]
  10. Casey D. (1996) Side effect profiles of new antipsychotic agents. J Clin Psychiatry 57(Suppl. 11): 40–45, discussion 46–52. [PubMed] [Google Scholar]
  11. Casey D., Sands E., Heisterberg J., Yang H. (2008) Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study. Psychopharmacology (Berl) 200: 317–331. [DOI] [PubMed] [Google Scholar]
  12. Citrome L. (2013) Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 9: 193–206. [DOI] [PubMed] [Google Scholar]
  13. Citrome L. (2015) Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 69: 978–997. [DOI] [PubMed] [Google Scholar]
  14. Correll C. (2010) From receptor pharmacology to improved outcomes: individualizing the selection, dosing, and switching of antipsychotics. Eur Psychiatry 25(Suppl. 2): S12–S21. [DOI] [PubMed] [Google Scholar]
  15. Correll C., Robinson D., Schooler N., Brunette M., Mueser K., Rosenheck R., et al. (2014) Cardio metabolic risk in first episode schizophrenia-spectrum disorder patients: baseline results from the RAISE-ETP study. JAMA Psychiatry 71: 1350–1363. [DOI] [PubMed] [Google Scholar]
  16. Correll C., Skuban A., Ouyang J., Hobart M., Pfister S., McQuade R., et al. (2015) Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry 172: 870–880. [DOI] [PubMed] [Google Scholar]
  17. Costa-Mattioli M., Sossin W., Klann E., Sonenberg N. (2009) Translational control of long lasting synaptic plasticity and memory. Neuron 61: 10–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Coyle J., Tsai G. (2004) The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berl) 174: 32–38. [DOI] [PubMed] [Google Scholar]
  19. Dahan L., Husum H., Mnie-Filali O., Arnt J., Hertel P., Haddjeri N. (2009) Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour. J Psychopharmacol 23: 177–189. [DOI] [PubMed] [Google Scholar]
  20. De Hert M., Detraux J., van Winkel R., Yu W., Correll C. (2012) Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 8: 114–126. [DOI] [PubMed] [Google Scholar]
  21. De Santis M., Pan B., Lian J., Huang X., Deng C. (2014) Different effects of bifeprunox, aripiprazole, and haloperidol on body weight gain, food and water intake, and locomotor activity in rats. Pharmacol Biochem Behav 124: 167–173. [DOI] [PubMed] [Google Scholar]
  22. Drouin C., Darracq L., Trovero F., Blanc G., Glowinski J., Cotecchia S., et al. (2002) Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates. J Neurosci 22: 2873–2884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Chappell P., Feltner D., Makumi C., Stewart M. (2012) Initial validity and reliability data on the Columbia-Suicide Severity Rating Scale. Am J Psychiatry 169: 662–663; author reply 663. [DOI] [PubMed] [Google Scholar]
  24. Ebdrup B., Rasmussen H., Arnt J., Glenthøj B. (2011) Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin Investig Drugs 20: 1211–1223. [DOI] [PubMed] [Google Scholar]
  25. Fawcett J., Barkin R. (1998) Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord 51: 267–285. [DOI] [PubMed] [Google Scholar]
  26. Fleischhacker W. (2005) Aripiprazole. Expert Opin Pharmacother 6: 2091–2101. [DOI] [PubMed] [Google Scholar]
  27. Freedman R. (2003) Schizophrenia. N Engl J Med 349: 1738–1749. [DOI] [PubMed] [Google Scholar]
  28. Gharabawi G., Bossie C., Turkoz I., Kujawa M., Mahmoud R., Simpson G. (2007) The impact of insight on functioning in patients with schizophrenia or schizoaffective disorder receiving risperidone long acting injectable. J Nerv Ment Dis 195: 976–982. [DOI] [PubMed] [Google Scholar]
  29. Goff D. (2015) Brexpiprazole: a new antipsychotic following in the footsteps of aripiprazole. Am J Psychiatry 172: 820–821. [DOI] [PubMed] [Google Scholar]
  30. Green M. (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153: 321–330. [DOI] [PubMed] [Google Scholar]
  31. Green M., Nuechterlein K., Gold J., Barch D., Cohen J., Essock S., et al. (2004) Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry 56: 301–307. [DOI] [PubMed] [Google Scholar]
  32. Gross G., Drescher K. (2012) The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. Handb Exp Pharmacol 213: 167–210. [DOI] [PubMed] [Google Scholar]
  33. Guy W. (ed) (1976) ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education and Welfare Publication (ADM) 76–338. Rockville, MD: National Institute of Mental Health. [Google Scholar]
  34. Haddjeri N., Blier P., de Montigny C. (1996) Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain. J Pharmacol Exp Ther 277: 861–871. [PubMed] [Google Scholar]
  35. Hagiwara H., Fujita Y., Ishima T., Kunitachi S., Shirayama Y., Iyo M., et al. (2008) Phencyclidine induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptor. Eur Neuropsychopharmacol 18: 448–454. [DOI] [PubMed] [Google Scholar]
  36. Hashimoto K. (2006) The NMDA receptor hypofunction hypothesis for schizophrenia and glycine modulatory sites on the NMDA receptors as potential therapeutic drugs. Clin Psychopharmacol Neurosci 4: 3–10. [Google Scholar]
  37. Hashimoto K. (2014) Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets 18: 1049–1063. [DOI] [PubMed] [Google Scholar]
  38. Hashimoto K., Fujita Y., Shimizu E., Iyo M. (2005) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol. Eur J Pharmacol 519: 114–117. [DOI] [PubMed] [Google Scholar]
  39. Hashimoto K., Ishima T. (2010) A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation factor eIF4AI. PLoS ONE 5: e15430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Hashimoto K., Ishima T. (2011) Neurite outgrowth mediated by translation elongation factor eEF1A1: a target for antiplatelet agent cilostazol. PLoS One 6: e17431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Hashimoto K., Malchow B., Falkai P., Schmitt A. (2013) Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 263: 367–377. [DOI] [PubMed] [Google Scholar]
  42. Howland R. (2015) Brexpiprazole: another multipurpose antipsychotic drug? J Psychosoc Nurs Ment Health Serv 53: 23–25. [DOI] [PubMed] [Google Scholar]
  43. Inada T., Beasley C., Tanaka Y., Walker D. (2003) Extra pyramidal symptom profiles assessed with the Drug-Induced Extra pyramidal Symptom Scale: comparison with Western scales in the clinical double-blind studies of schizophrenic patients treated with either olanzapine or haloperidol. Int Clin Psychopharmacol 18: 39–48. [DOI] [PubMed] [Google Scholar]
  44. Ishima T., Futamura T., Ohgi Y., Yoshimi N., Kikuchi T., Hashimoto K. (2015) Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin–dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors. Eur Neuropsychopharm 25: 505–511. [DOI] [PubMed] [Google Scholar]
  45. Ishima T., Hashimoto K. (2012) Potentiation of nerve growth factor induced neurite outgrowth in PC 12 cells by ifenprodil: role of sigma-1and IP3 receptors. PLoS ONE 7: e37989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ishima T., Iyo M., Hashimoto K. (2012) Neurite outgrowth mediated by the heat shock protein HSP90α: a novel target for the antipsychotic drug aripiprazole. Transl Psychiatry 2: e170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Itoh K., Ishima T., Kehler J., Hashimoto K. (2011) Potentiation of NGF-induced neurite outgrowth in PC12 cells by papaverine: role played by PLC-gamma and IP3 receptors. Brain Res 1377: 32–40. [DOI] [PubMed] [Google Scholar]
  48. Kane J., Skuban A., Ouyang J., Hobart M., Pfister S., McQuade R., et al. (2015) A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizphr Res 164: 127–135. [DOI] [PubMed] [Google Scholar]
  49. Kay S., Opler L., Fiszbein A. (1999) Positive and Negative Syndrome Scale (PANSS) Rating Criteria. North Tonawanda, NY: Multi-Health Systems. [Google Scholar]
  50. Kikuchi T., Tottori K., Uwahodo Y., Hirose T., Miwa T., Oshiro Y., et al. (1995) 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther 274: 329–336. [PubMed] [Google Scholar]
  51. Kiss B., Horváth A., Némethy Z., Schmidt E., Laszlovszky I., Bugovics G., et al. (2010) Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther 333: 328–340. [DOI] [PubMed] [Google Scholar]
  52. Kleven M., Koek W. (1996) Differential effects of direct and indirect dopamine agonists on eye blink rate in cynomolgus monkeys. J Pharmacol Exp Ther 279: 1211–1219. [PubMed] [Google Scholar]
  53. Kroeze W., Hufeisen S., Popadak B., Renock S., Steinberg S., Ernsberger P., et al. (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28: 519–526. [DOI] [PubMed] [Google Scholar]
  54. Kuroki T., Nagao N., Nakahara T. (2008) Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis. Prog Brain Res 172: 199–212. [DOI] [PubMed] [Google Scholar]
  55. Laoutidis Z., Kioulos K. (2014) Antipsychotic induced elevation of creatine kinase: a systematic review of the literature and recommendations for the clinical practice. Psychopharmacology (Berl) 231: 4255–4270. [DOI] [PubMed] [Google Scholar]
  56. Laoutidis Z., Luckhaus C. (2014) 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol 17: 823–832. [DOI] [PubMed] [Google Scholar]
  57. Leucht S., Cipriani A., Spineli L., Mavridis D., Orey D., Richter F., et al. (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple treatments meta-analysis. Lancet 382: 951–962. [DOI] [PubMed] [Google Scholar]
  58. Lieberman J., Perkins D., Belger A., Chakos M., Jarskog F., Boteva K., et al. (2001) The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 50: 884–897. [DOI] [PubMed] [Google Scholar]
  59. Lindenmayer J., Bernstein-Hyman R., Grochowski S., Bark N. (1995) Psychopathology of Schizophrenia: initial validation of a 5-factor model. Psychopathology 28: 22–31. [DOI] [PubMed] [Google Scholar]
  60. Maeda K., Lerdrup L., Sugino H., Akazawa H., Amada N., McQuade R., et al. (2014a) Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 350: 605–614. [DOI] [PubMed] [Google Scholar]
  61. Maeda K., Sugino H., Akazawa H., Amada N., Shimada J., Futamura T., et al. (2014b) Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 350: 589–604. [DOI] [PubMed] [Google Scholar]
  62. Mamo D., Graff A., Mizrahi R., Shammi C., Romeyer F., Kapur S. (2007) Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 164: 1411–1417. [DOI] [PubMed] [Google Scholar]
  63. Marcus M., Wiker C., Frånberg O., Konradsson-Geuken A., Langlois X., Jardemark K., et al. (2010) Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission. Int J Neuropsychopharmacol 13: 891–903. [DOI] [PubMed] [Google Scholar]
  64. Marder S., Davis J., Chouinard G. (1997) The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 58: 538–546. [DOI] [PubMed] [Google Scholar]
  65. Melkersson K. (2006) Serum creatine kinase levels in chronic psychosis patients: a comparison between atypical and conventional antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 30: 1277–1282. [DOI] [PubMed] [Google Scholar]
  66. Meltzer H. (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21(2 Suppl.): 106S–115S. [DOI] [PubMed] [Google Scholar]
  67. Meltzer H. (2012) Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb Exp Pharmacol 212: 87–124. [DOI] [PubMed] [Google Scholar]
  68. Minase T., Ishima T., Itoh K., Hashimoto K. (2010) Potentiation of nerve growth factor induced neurite out growth by the ROCK inhibitor Y-27632: a possible role of IP3 receptors. Eur J Pharmacol 648: 67–73. [DOI] [PubMed] [Google Scholar]
  69. Mongeau R., Blier P., deMontigny C. (1993) In vivo electrophysiological evidence for tonic activation by endogenous noradrenaline of alpha 2-adrenergic receptors on 5-hydroxytryptamine terminals in the rat hippo campus. Naunyn Schmiedebergs Arch Pharmacol 347: 266–272. [DOI] [PubMed] [Google Scholar]
  70. Monti J. (2010) Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects. Drugs Today (Barc) 46: 183–193. [DOI] [PubMed] [Google Scholar]
  71. Montoya A., Valladares A., Lizán L., San L., Escobar R., Paz S. (2011) Validation of the excited component of the Positive and Negative Syndrome Scale (PANSSEC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room. Health Qual Life Outcomes 9: 18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Mørk A., Witten L., Arnt J. (2009) Effect of sertindole on extracellular dopamine and glutamate in the frontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Eur J Pharmacol 206: 39–49. [DOI] [PubMed] [Google Scholar]
  73. Morosini P., Magliano L., Brambilla L., Ugolini S., Pioli R. (2000) Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand 101: 323–329. [PubMed] [Google Scholar]
  74. Nakaya M., Suwa H., Ohmori K. (1999) Latent structures underlying schizophrenic symptoms: a five-dimensional model. Schizophr Res 39: 39–50. [DOI] [PubMed] [Google Scholar]
  75. Nelson J., Papakostas G. (2009) Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 166: 980–991. [DOI] [PubMed] [Google Scholar]
  76. Newman-Tancredi A., Cussac D., Depoortere R. (2007) Neuropharmacological profile of bifeprunox: merits and limitations in comparison with other third generation antipsychotics. Curr Opin Investig Drugs 8: 539–554. [PubMed] [Google Scholar]
  77. Newman-Tancredi A., Kleven M. (2011) Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties. Psychopharmacology (Berl) 216: 451–473. [DOI] [PubMed] [Google Scholar]
  78. Niitsu T., Iyo M., Hashimoo K. (2012) Sigma-1 receptor agonists as therapeutic drugs for cognitive impairments in neuropsychiatric disease. Curr Pharm Des 18: 875–883. [DOI] [PubMed] [Google Scholar]
  79. Nishimura T., Ishima T., Iyo M., Hashimoto K. (2008) Potentiation of nerve growth factor induced neurite outgrowth by fluvoxamine: role of sigma-1receptors, IP3 receptors and cellular signaling pathways. PLoS ONE 3: e2558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Ogren S., Eriksson T., Elvander-Tottie E., D’Addario C., Ekström J., Svenningsson P., et al. (2008) The role of 5-HT1A receptors in learning and memory. Behav Brain Res 195: 54–77. [DOI] [PubMed] [Google Scholar]
  81. Oosterhof C., Mansari M., Blier P. (2014) Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization. J Pharmacol Exp Ther 351: 585–595. [DOI] [PubMed] [Google Scholar]
  82. Posner K., Brown G., Stanley B., Brent D., Yershova K., Oquendo M., et al. (2011) The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168: 1266–1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Potkin S., Raoufinia A., Mallikaarjun S., Bricmont P., Peters-Strickland T., Kasper W., et al. (2013) Safety and tolerability of once monthly aripiprazole treatment initiation in adults with schizophrenia stabilized on selected atypical oral antipsychotics other than aripiprazole. Curr Med Res Opin 29: 1241–1251. [DOI] [PubMed] [Google Scholar]
  84. Roth B., Sheffler D., Kroeze W. (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3: 353–359. [DOI] [PubMed] [Google Scholar]
  85. Rummel-Kluge C., Komossa K., Schwarz S., Hunger H., Schmid F., Kissling W., et al. (2012) Second-generation antipsychotic drugs and extra pyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 38: 167–177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Sallinen J., Holappa J., Koivisto A., Kuokkanen K., Chapman H., Lehtimäki J., et al. (2013) Pharmacological characterization of a structurally novel a2C-adrenoceptor antagonist ORM-10921 and its effects in neuropsychiatric models. Basic Clin Pharmacol Toxicol 113: 239–249. [DOI] [PubMed] [Google Scholar]
  87. Simpson G., Angus J. (1970) A rating scale for extra pyramidal side effects. Acta Psychiatr Scand Suppl 212: 11–19. [DOI] [PubMed] [Google Scholar]
  88. Snigdha S., Horiguchi M., Huang M., Li Z., Shahid M., Neill J., et al. (2010) Attenuation of phencyclidine induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine (2A) receptor inverse agonist. J Pharmacol Exp Ther 332: 622–631. [DOI] [PubMed] [Google Scholar]
  89. Stockmeier C., DiCarlo J., Zhang Y., Thompson P., Meltzer H. (1993) Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J Pharmacol Exp Ther 266: 1374–1384. [PubMed] [Google Scholar]
  90. Sumiyoshi T., Matsui M., Nohara S., Yamashita I., Kurachi M., Sumiyoshi C., et al. (2001a) Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry 158: 1722–1725. [DOI] [PubMed] [Google Scholar]
  91. Sumiyoshi T., Matsui M., Yamashita I., Nohara S., Kurachi M., Uehara T., et al. (2001b) The effect of tandospirone, a serotonin-1A agonist, on memory function in schizophrenia. Biol Psychiatry 49: 861–868. [DOI] [PubMed] [Google Scholar]
  92. Thase M., Youakim J., Skuban A., Hobart M., Zhang P., Legacy S., et al. (2014). Efficacy and safety of adjunctive brexpiprazole (OPC-34712) in major depressive disorder: results of two pivotal clinical studies. Neuropsychopharmacology 39: S357. [Google Scholar]
  93. Thase M., Youakim J., Skuban A., Hobart M., Augustine C., Zhang P., et al. (2015a) Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry 76: 1224–1231. [DOI] [PubMed] [Google Scholar]
  94. Thase M., Youakim J., Skuban A., Hobart M., Zhang P., McQuade R., et al. (2015b) Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry 76: 1232–1240. [DOI] [PubMed] [Google Scholar]
  95. US FDA (2015) Drugs. Available at: http://www.fda.gov/Drugs/default.htm (accessed 2 October 2015).
  96. US FDA News Release (2015) FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat major depressive disorder. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm454647.htm (accessed 20 July 2015).
  97. Van der Gaag M., Hoffman T., Remijsen M., Hijman R., de Haan L., van Meijel B., et al. (2006) The five-factor model of the Positive and Negative Syndrome Scale II: a ten-fold cross-validation of a revised model. Schizophr Res 85: 280–287. [DOI] [PubMed] [Google Scholar]
  98. Villegier A., Blanc G., Glowinski J., Tassin J. (2003) Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors. Pharmacol Biochem Behav 76: 267–274. [DOI] [PubMed] [Google Scholar]
  99. Von Knorring L., Lindstrom E. (1995) Principal components and further possibilities with the PANSS. Acta Psychiatr Scand Suppl 388: 5–10. [DOI] [PubMed] [Google Scholar]
  100. Wong E., Nikam S., Shahid M. (2008) Multi and single-target agents for major psychiatric diseases: therapeutic opportunities and challenges. Curr Opin Investig Drugs 9: 28–36. [PubMed] [Google Scholar]
  101. Yokoi F., Gründer G., Biziere K., Stephane M., Dogan A., Dannals R., et al. (2002) Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C] raclopride. Neuropsychopharmacology 27: 248–259. [DOI] [PubMed] [Google Scholar]
  102. Yoshimi N., Fujita Y., Ohgi Y., Futamura T., Kikuchi T., Hashimoto K. (2014) Effects of brexpiprazole, a novel serotonin–dopamine activity modulator, on phencyclidine induced cognitive deficits in mice: a role for serotonin5-HT1A receptors. Pharmacol Biochem Behav 124: 245–249. [DOI] [PubMed] [Google Scholar]
  103. Yoshimi N., Futamura T., Hashimoto K. (2015) Improvement of dizocilpine induced social recognition deficits in mice by brexpiprazole, a novel serotonin–dopamine activity modulator. Eur Neuropsychopharm 25: 356–364. [DOI] [PubMed] [Google Scholar]

Articles from Therapeutic Advances in Psychopharmacology are provided here courtesy of SAGE Publications

RESOURCES