672136

research-article2016
TPP0010.1177/2045125316672136Therapeutic Advances in PsychopharmacologyJS Frankel and TL Schwartz

Therapeutic Advances in Psychopharmacology Review

Brexpiprazole and cariprazine:

Ther Adv Psychopharmacol

2017, Vol. 7(1) 29­–41

distinguishing two new atypical DOI: 10.1177/

2045125316672136

antipsychotics from the original dopamine

© The Author(s), 2016.
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stabilizer aripiprazole
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Joshua S. Frankel and Thomas L. Schwartz

Abstract
Background: Brexpiprazole and cariprazine are the latest US Food and Drug Administration
approved atypical antipsychotics available in the United States. Both function as partial
agonists of the dopamine-2 receptor (D2R), a mechanism of action shared with aripiprazole.
However, all three differ in their affinities for the D2R as well as for serotonin receptors
(5-HTRs). This paper seeks to delineate these pharmacodynamic and clinical differences
amongst the three dopamine partial agonist atypical antipsychotic drugs.
Methods: PubMed and clinicaltrials.gov searches were used to generate preclinical and
clinical evidence for review. Data derived from animal models and human subjects were used
to provide insight on clinical mechanisms and adverse effect potentials. Clinical trial data
were reviewed to compare clinical efficacy and adverse effects.
Results: Efficacies among the three drugs are comparable for their shared indications. Side-
effect profile and underlying pharmacodynamic mechanism of action for each drug may differ.
Conclusion: Partial agonism of the D2R is a similarity of the three drugs reviewed. Each drug
varies in affinity for both the D2R and a diverse group of 5-HTRs, generating a distinct profile of
clinical indications and adverse effects for each.

Keywords: brexpiprazole, cariprazine, aripirazole, antipsychotic, dopamine partial agonist

Introduction The typical antipsychotics were not selective as Correspondence to:

Thomas L. Schwartz, MD
In the mid-twentieth century, typical antipsychot- they provided both efficacy and higher rates of Department of Psychiatry,
ics, heralded by the ‘anti-histamine’ chlorproma- EPS. To lower EPS, the check and balance selec- SUNY Upstate Medical
University, 750 E. Adams
zine, relieved patients of psychotic symptoms, but tivity provided by 5-HT2AR antagonism allows Street, Syracuse, NY
at the cost of frequent extrapyramidal symptoms greater dopamine activity to remain within the 13210, USA
schwartt@upstate.edu
(EPS), tardive dyskinesia (TD), and hyperprol- nigrostriatal pathway while preferentially lowering Joshua S. Frankel, MD
actinemia. In the early 1990s, risperidone, the first psychotic symptoms theoretically by preferentially Department of Psychiatry,
SUNY Upstate Medical
of a class of newer, atypical antipsychotics, reduced dampening the mesolimbic pathway. The advan- University, Syracuse, NY,
the frequency of these effects, due chiefly to antag- tage of atypical antipsychotics is a match in efficacy USA
onism of the 2A serotonin receptor (5-HT2AR). with the typical antipsychotics but allowing for
Antagonizing 5-HT2AR leads indirectly to down- much fewer EPS [Stahl, 2013]. This accomplish-
stream effects that raise dopamine neurotransmis- ment led to obsolescence for many of the older
sion in EPS-prone brain areas (e.g. nigrostriatal typical antipsychotics, shifting their use downward
system). For example, typical antipsychotic- along most guideline algorithms [Lehman et al.
induced shortages of dopamine activity along the 2004].
nigrostriatal pathway may lead to Parkinsonism,
dystonia, akathisia, or neuroleptic malignant syn- Within a decade of the emergence of the first
drome. Simultaneously, lower dopamine transmis- novel atypical risperidone, aripiprazole intro-
sion in the mesolimbic circuits alleviates psychosis. duced yet another novel mechanism. Perhaps

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Therapeutic Advances in Psychopharmacology 7(1)

Table 1. US Food and Drug Administration approved indications for aripiprazole, brexpiprazole, and
cariprazine [Actavis, 2015; Alkermes, 2015; Otsuka, 2014, 2015a, 2015b].

Aripiprazole Brexpiprazole Cariprazine

Schizophrenia (adults)   
Schizophrenia (adolescents) 
Schizophrenia or bipolar mania associated agitation 
(adults) via intramuscular route
Schizophrenia depot injection 
Bipolar disorder (adults and pediatric patients), acute 
monotherapy for mania
Bipolar disorder (adults and pediatric patients), acute 
adjunctive treatment to lithium or valproate for mania
Bipolar disorder (adults only), acute treatment of manic or  
mixed episodes
Bipolar disorder (adults only), maintenance treatment 
Adjunctive treatment of major depressive disorder (adults)  
Tourette’s disorder (pediatric patients) 
Irritability associated with autistic spectrum disorder 
(pediatric patients)

more atypical than its counterparts, aripiprazole
is a partial agonist of the D2R. Until 2015, it was
the only available agent within the class of atypi-
cal antipsychotics that could both stimulate and
inhibit dopamine at the moment it engaged the
D2R. At high DA concentrations, aripiprazole
lowers DA neuronal firing, while at low concen-
trations it increases DA firing. At the time, this
mechanism of action was called ‘dopamine stabi-
lization’ because a single drug could increase or
decrease neuronal firing as needed. The newly
approved brexpiprazole and cariprazine also uti-
lize this D2 partial agonism mechanism.
The partial agonist effect is interesting in that it
allows an intermediate level of dopaminergic neu-
ronal tone between full agonist and antagonist of
the D2R. The goal of this intermediate level is to
remain beneath the threshold development of
positive symptoms induced by excessive dopa-
mine, but not too low, ideally to avoid adverse
effects such as EPS [Stahl, 2013].
Comparative approved indications
Aripiprazole has been approved for schizophrenia
in both adults and adolescents; acute bipolar
mania as either monotherapy or as an adjunctive
therapy to lithium or valproate for both adults
and pediatric patients; maintenance treatment
for bipolar I disorder in adults; major depressive
disorder in adults as adjunctive therapy to anti-
depressants; irritability associated with autism
spectrum disorder in pediatric patients; Tourette’s
disorder in pediatric patients; and via intramus-
cular injection for agitation associated with schiz-
ophrenia or bipolar mania in adults as well as
long-acting injectable depot forms for schizophre-
nia [Alkermes, 2015; Otsuka, 2014, 2015a].
Brexpiprazole has received approval for treating
major depressive disorder in adults as an adjunc-
tive therapy to antidepressants; and to treat schiz-
ophrenia in adults [Otsuka, 2015b].
Cariprazine is approved for treating acute mania
or mixed episodes associated with bipolar I disor-
der in adults; and for treating schizophrenia in
adults [Actavis, 2015]. A recent study demon-
strated the efficacy of cariprazine in alleviating cer-
tain negative symptoms of schizophrenia as well
[Debelle et al. 2015]. Table 1 Summarizes the
FDA approved indications for these three drugs.
Comparative pharmacodynamic
mechanisms
All three drugs interact with the following recep-
tors: partial agonism of D2R, the dopamine-3
receptor (D3R), and the serotonin-1A receptor
(5-HT1AR); and antagonism of the serotonin
receptors 2A, 2C, and 7 (5-HT2AR, 5-HT2CR,
5-HT7R, respectively), the histamine-1 receptor,
(H1R), the muscarinic-1 cholinergic receptor
(M1R), and the α1 adrenergic receptor (α1R)
[Stahl, 2013]. Theoretically, each of these

30 http://tpp.sagepub.com

interactions may allow for symptomatic efficacy
or clinical side effects to occur.
For D2R partial agonism, brexpiprazole has the
strongest affinity followed by aripiprazole and
cariprazine [Actavis, 2015; Otsuka, 2014, 2015b].
Regarding D3R partial agonism, cariprazine has
the strongest affinity followed by aripiprazole and
brexpiprazole [Actavis, 2015; Otsuka, 2014,
2015b]. In high DA areas of the brain, D3R par-
tial agonism has the net effect of dampening DA
neuronal firing, thus lowering psychosis or mania.
Theoretically, higher affinity should yield stronger
clinical effects. There may also be an association
with increased cortical static tone for alertness
and wakefulness if the D3R is agonized. Evidence
amassed so far includes statistically and clinically
significant improvements in positive symptoms of
schizophrenia among subjects found to possess
DRD3 polymorphisms for the D3R gene, and this
D3 property may be implicated as a risk to devel-
oping schizophrenia symptoms [Adams et al.
2008]. Animal models have demonstrated that
negative symptoms improve, including cognition
and social behavior, with D3R agonism [Gross,
2012]. Cariprazine, in particular, is distinguished
from the other two drugs in its predilection for
and relative strength in binding the D3R [Kiss
et al. 2010]. Cariprazine selectively binds the D3R
at comparatively lower doses. As such, this sug-
gests that D3R partial agonism in the cortex may
improve dopaminergic function and thus help
improve negative symptoms of schizophrenia or
the vegetative symptoms of depression.
Interestingly, there are more serotonin receptors
being manipulated by these atypical agents com-
pared with dopamine receptor modulation. In
regard to 5-HT1AR partial agonism, brexpipra-
zole has the strongest affinity followed by ari-
piprazole and cariprazine [Actavis, 2015; Otsuka,
2014, 2015b]. Partial agonism of the 5-HT1AR
may increase dopamine release in the mesocorti-
cal pathway, similar to the partial agonism of
D3R. Therefore, partial agonism of either D3R or
5-HT1AR may account for antidepressant effects.
This mechanism is utilized by the psychotropics
buspirone, vilazodone, and vortioxetine. For
5-HT2AR antagonism, brexpiprazole has the
greatest affinity followed by aripiprazole and
cariprazine [Actavis, 2015; Otsuka, 2014, 2015b].
In this case, it is antagonism that ultimately allows
greater amounts of DA to act with in the nigros-
triatal system, thus lowering EPS. For 5-HT2CR
antagonism, aripiprazole has the strongest affinity
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JS Frankel and TL Schwartz
followed by brexpiprazole and cariprazine
[Actavis, 2015; Otsuka, 2014, 2015b].
Concerning 5-HT7R antagonism, brexpiprazole
has the strongest affinity followed by aripiprazole
and cariprazine [Actavis, 2015; Otsuka, 2014,
2015b]. Antagonism of the 5-HT2CR and the
5-HT7R are both thought to provide antidepres-
sant activity [Stahl, 2013]. 5-HT2C blockade
likely increases frontocortical NE and DA similar
to the antidepressant mirtazapine [Gobert et al.
2000]. 5-HT7R antagonism likely improves cog-
nition and circadian function as noticed in the
antidepressant effects of vortioxetine and lurasi-
done [Hedlund et al. 2005].
The above properties may enhance clinical effec-
tiveness. The next properties may yield side
effects. Analysis of H1R antagonism suggests that
brexpiprazole has the strongest affinity followed
by cariprazine and aripiprazole [Actavis, 2015;
Otsuka, 2014, 2015b]. Antihistaminergic side
effects include sedation and weight gain (some-
times associated with the cardiometabolic seque-
lae of atypical antipsychotics). Less antagonism of
the H1R means fewer antihistaminergic effects.
Aripiprazole is the drug with the weakest affinity,
suggesting a tolerability advantage here. M1R
antagonism (all three drugs show extremely weak
affinity and therefore little antagonism) may cause
anticholinergic effects, including impaired accom-
modation (cycloplegia), increased intraocular
pressure, xerostomia, constipation, tachycardia
and urinary retention. For α1R antagonism, brex-
piprazole has the strongest affinity followed by
aripiprazole and cariprazine [Actavis, 2015;
Otsuka, 2014, 2015b]. Again, cariprazine, with
the weakest affinity is expected to have the least
antagonism and theoretically the lowest rate of
anti-α1R effects, which include sedation and
hypotension. Interestingly, high affinity here may
have an advantage if treating patients who have
nightmares, akin to the effect of the α1R antago-
nist prazosin.
In summary, and based upon official US Food
and Drug Administration (FDA) values as found
in package inserts, the binding affinities, Ki (nM),
of these receptors are summarized in Table 2
[Actavis, 2015; Otsuka, 2014, 2015b]:
Comparative pharmacokinetics and dosing
Aripiprazole’s chemical structure is shown in
Figure 1. Initial dosage varies with the indication.
The lower initial dose of 2 mg/day is used for
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Therapeutic Advances in Psychopharmacology 7(1)

Table 2. Binding affinities of aripiprazole, brexpiprazole, cariprazine, and the clinical properties of the receptors.

Aripiprazole Brexpiprazole Cariprazine Therapeutic effects Adverse effects

D2 0.34 0.30 0.49 Antipsychotic EPS, tardive dyskinesia,
akathesia, NMS
hyperprolactinemia
D3 0.8 1.1 0.085 Antipsychotic (including
negative symptoms),
antimanic, antidepressant
5-HT1A 1.7 0.12 2.6 Antidepressant, anxiolytic
5-HT2A 3.4 0.47 18.8 Anti-EPS
5-HT2C 15 34 134 Antidepressant
5-HT7 29 3.7 111 Antidepressant
H1 61 19 23.2 Anxiolytic, anti-insomnia Weight gain sedation
M1 >1000 >1000 >1000 Opposes EPS Xerostomia, constipation, blurry
vision, cognitive dysfunction,
falls (e.g. older adults)
α1 57 3.8 155 Antihypertensive Sedation, orthostasis
Comparing the three partial D2 agonists:
(1) Aripiprazole has the greatest affinity for 5-HT2CR; it has the weakest affinity for H1R. Theoretically, this suggests it may be less associated with
metabolic symptoms and perhaps elevate monoamines for better antidepressant effects, therapeutically speaking. It may be the least sedating.
(2) Brexpiprazole shows the greatest affinity for D2R, 5-HT1AR, 5-HT2AR, 5-HT7R, H1R, and α1R; it has the weakest affinity for D3R. This suggests
the possibility that it can both inhibit and enhance dopamine activity to a higher degree, treating either psychosis or depression. The serotonin
modulation is highly suggestive of antidepressant activity.
(3) Cariprazine shows the greatest affinity for D3R; it is the weakest in affinity for D2R, 5-HT1AR, 5-HT2AR, 5-HT7R, and α1R. This may promote a fair
amount of dopamine activity and act as an antidepressant. The serotonin modulation is highly suggestive of antidepressant activity.
EPS, extrapyramidal symptoms; NMS, neuroleptic malignant syndrome.

schizophrenia in adolescents, bipolar mania in
pediatric patients, adjunct treatment for depres-
sion (2–5 mg), irritability associated with autism,
and for Tourette’s disorder. The intramuscular
injection is initially 9.75 mg for agitation associ-
ated with either schizophrenia or bipolar mania in
adults; if the oral route is used instead, then initial
dosage starts at 10–15 mg/day. Recommended
therapeutic doses range from 5 mg (Tourette’s
disorder, irritability associated with autism, and
major depression adjunctive treatment) to 15 mg
(bipolar mania and schizophrenia in adults) per
day, with maximum daily doses ranging from
10 mg (Tourette’s disorder) up to 30 mg (bipolar
mania and schizophrenia among all ages). Tablets
are available in doses of 2 mg, 5 mg, 10 mg, 15 mg,
20 mg, and 30 mg; orally disintegrating tablets of
10 and 15 mg, oral solution of 1 mg/ml, and injec-
tion of 9.75 mg/1.3 ml [Otsuka, 2014]. Depot
form is available in 300 or 400 mg lyophilized
powder, dosed monthly, and 441, 662, or 882 mg
single-use prefilled syringes for aripiprazole
lauroxil either monthly or every 6 weeks (882 mg
only) [Otsuka, 2015a; Alkermes, 2015]. Oral
doses are taken once daily without requiring
food. Injections for acute agitation require 2 h
between administrations. Metabolism is via
hepatic Cytochrome (CYP) P4503A4 (CYP3A4)
and 2D6. Known CYP2D6 poor metabolizers or
those concurrently taking strong CYP2D6 inhibit-
ers should take half the usual dose and a quarter
dose if a strong inhibitor of CYP-3A4 is copre-
scribed; coadministration of a strong CYP3A4
inducer calls for a doubling of the usual aripipra-
zole dose. Steady state is achieved in 14–15 days,
when the pharmacokinetics is dose proportional.
The half life is 75 h for the parent compound and
94 h for its major metabolite, dehydroaripiprazole,
which shows similar affinity for D2 receptors. Oral
bioavailability is 87% [Alkermes, 2015; Otsuka,
2014, 2015a].
Brexpiprazole’s chemical structure is shown in
Figure 2. The initial dose for schizophrenia is 1 mg/
day, with a recommended dose of 2–4 mg/day with
4 mg/day as the maximum daily dose (3 mg/day if
there is comorbid moderate-to-severe hepatic or
renal impairment). The starting dose for major
depression is 0.5–1 mg/day up to a recommended
2 mg/day; maximum dose is 3 mg/day (unless mod-
erate or severe renal or hepatic impairment, when
the maximum dose is 2 mg/day). Tablets are avail-
able in 0.25, 0.5, 1, 2, 3, and 4 mg. Metabolism is
mediated by CYP3A4 and CYP2D6. Known
CYP2D6 poor metabolizers or those taking a drug
with strong inhibition of CYP2D6 and CYP3A4

32 http://tpp.sagepub.com

are instructed to take half the usual dose similar to
aripiprazole; if both criteria are met, then the dose
is quartered. CYP3A4-inducing drugs taken con-
currently should double the dose over 1 or 2 weeks.
Oral bioavailability is 95%. The half life of brex-
piprazole is 91 h, with steady-state level reached by
10–19 days, which is longer than that of aripipra-
zole. Administration requires no food. When
highly protein bound (>99%), brexpiprazole did
not affect warfarin, diazepam, or digoxin dosing
[Otsuka, 2015b].
Cariprazine’s chemical structure is shown in Figure
3. The starting dose is 1.5 mg/day for both schizo-
phrenia and bipolar mania. The recommended
dose is between 1.5 and 6 mg/day for schizophrenia
and 3–6 mg/day for bipolar mania. Capsules are
available in doses of 1.5 mg, 3 mg, 4.5 mg, and
6 mg. Cariprazine is metabolized by CYP3A4 and
those also taking a CYP3A4 strong inhibitor are
instructed to take half the usual dose of cariprazine.
Unlike the previous two drugs, this drug is not a
2D6 substrate. The drug is highly protein bound
(97%). The reported half life is a range of 2–4 days,
which is either shorter or more prolonged than ari-
piprazole’s 75 h half life for the parent compound.
However, cariprazine’s active metabolite, didesme-
thyl, is longer lasting with a half life between 1 and
3 weeks. Peak plasma concentrations of cariprazine
are achieved in 3–6 h. Cariprazine’s steady state is
10–20 days [Actavis, 2015].
In summary, the longest half life, if its active
metabolite is included, is cariprazine’s, which is
as long as 3 weeks (a range of 1–3 weeks); ari-
piprazole and brexpiprazole follow with 94 and
91 h, respectively. If only the parent compound is
considered, then cariprazine, with as long as 4
days (2–4-day range), still has the longest half life,
but this time aripiprazole has the shortest half life
with 75 h, with brexpiprazole at 91 h. Consequently,
cariprazine’s range (parent compound) suggests
that it could be either the longest or the shortest of
the three, while it is clearly the longest lasting
given the active metabolite.
Collectively, this subclass of atypical antipsychot-
ics have the longest-ranging half lives.
Clinical studies
Aripiprazole
Schizophrenia. Four trials all gave rise to statis-
tically significant changes in scores using the
Positive and Negative Syndrome Scale (PANSS)
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JS Frankel and TL Schwartz
[Cutler et al. 2006; Findling et al. 2008; Kane
et al. 2002; McEvoy et al. 2007; Potkin et al.
2003]. A 4-week trial reduced the PANSS score
by nearly 16 at 15 mg/day and 11 at 30 mg/day
[Kane et al. 2002]. This was greater than pla-
cebo by approximately 13 and 9 points, respec-
tively [Kane et al. 2002]. A second study,
comparing 20 and 30 mg strengths, reduced the
score by 15 and 14 points, with improvements
over placebo of 10 and 9, respectively [Potkin
et al. 2003]. The third, comparing the various
strengths evaluated in the previously described
studies, revealed changes for 10, 15, and 20 mg/
day of 15, 12, and 14, respectively, improve-
ments of 13, 9 and 12 compared with placebo,
respectively [McEvoy et al. 2007]. In a fourth
study, lower strength dosages were included,
with 2, 5, and 10 mg, yielding reductions of 8,
11, and 11, or 3, 5, and 5 compared with pla-
cebo, respectively [Cutler et al. 2006]. Addition-
ally, a 6-week study of younger patients treated
with 10 and 30 mg/day lowered the PANSS
score by 27 and 29 or 6 and 7, respectively,
compared with placebo, yielding FDA approval
for use in patients from the age of 13 [Findling
et al. 2008].
Bipolar disorder. For the acute treatment of
manic and mixed episodes associated with bipolar
disorder, the Young Mania Rating Scale (YMRS)
was the primary endpoint. Aripiprazole was
assessed in four studies with dosages between 15
and 30 mg [Keck et al. 2003, 2009; Sachs et al.
2006; Young et al. 2009]. The first study, with
15 mg/day, yielded reductions of 13 (an improve-
ment of 5 over placebo) [Sachs et al. 2006]. The
second study yielded decreases of 8 (5 compared
with placebo) [Keck et al. 2003]. The third study,
a reduction in score of 13, or 4-point greater
reduction than placebo [Keck et al. 2009]. The
fourth study led to a reduction of 12, a decrease
of 2 more than Young and colleagues [Young et al.
2009]. A separate study for pediatric patients
used 10 and 30 mg strengths and after 4 weeks
yielded reductions of 14 and 15, or differences
from placebo of 6 and 7, respectively [Findling
et al. 2013]. As adjunctive treatment in bipolar
disorder, aripiprazole or placebo was given to
patients already taking lithium or valproate at
therapeutic levels but who were not clinically
responding after 2 weeks; reductions of 13, a dif-
ference of 3 over placebo resulted, resulted with
statistical significance [Vieta et al. 2008].
Major depressive disorder. To assess efficacy
as adjunctive treatment of major depressive
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Therapeutic Advances in Psychopharmacology 7(1)
disorder, subjects who had initially been tested
and confirmed as treatment resistant to either
selective-serotonin reuptake inhibitor (SSRI) or
serotonin-norepinephrine reuptake inhibitor
(SNRI) alone were randomized to receive either
an adjunctive placebo or adjunctive aripiprazole,
at strengths between 2 and 20 mg/day [Marcus
et al. 2008]. The primary endpoint was the change,
over 6 weeks, in the Montgomery–Asberg Depres-
sion Rating Scale (MADRS). Adjunctive aripip-
razole resulted in a MADRS score reduction of 8,
compared with 6 for placebo [Marcus et al. 2008].
A second study, also 6 weeks in duration and
allowing up to 20 mg, reduced the MADRS score
by 9 versus the placebo’s 6 [Berman et al. 2007].
Autism spectrum disorder. Aripiprazole gained
approval to treat irritability associated with
autism spectrum disorder. Using the Aberrant
Behavior Checklist’s (ABC) subscale for irritabil-
ity, improvements over an 8-week period were
assessed in two studies between those receiving
aripiprazole and placebo [Marcus et al. 2009;
Owen et al. 2009]. The primary efficacy outcome
was mean change in score. In the first study, with
subjects receiving between 2 and 15 mg/day, by
week eight there was a reduction by 13 for aripip-
razole versus 5 for placebo [Owen et al. 2009].
The second study stratified according to dosages
of 5, 10, and 15 mg, all resulted in significant
ABC score reductions of 12, 13, and 14 com-
pared with an average placebo reduction of 8
[Marcus et al. 2009].
Tourette’s disorder. For treating young patients
with Tourette’s disorder, two trials assessed as pri-
mary outcomes decreases in the Yale Global Tic
Severity Score [Otsuka, 2015c;Yoo et al. 2013]. In
the first study, starting at 2 mg, patients under
50 kg ultimately received low dose aripiprazole of
5 mg and those over 50 kg a higher target dose of
20 mg; over 8 weeks, both low- and high-dose
aripiprazole achieved statistical significance,
approximately doubling the reduction in Total Tic
Score (TTS) compared with placebo [Otsuka,
2015c]. The second study, over 10 weeks, also
started at 2 mg but allowed for all subjects to
titrate up to 20 mg. The result was a statistically
significant five-point reduction in the TTS [Yoo
et al. 2013].
Acute agitation in schizophrenia or bipolar
mania. For acute intramuscular injection for agi-
tation associated with either schizophrenia or
bipolar mania, the primary efficacy measure
34
compared values of PANSS (the primary efficacy
measure) at baseline versus 2 h post injection. A
secondary endpoint was Clinical Global Impres-
sions Severity scale (CGI-S). Two trials employed
haloperidol as comparator [Andrezine et al. 2006;
Tran-Johnson et al. 2007]. The first trial compared
four different strengths (1, 5.25, 9.75, and 15 mg),
while the second trial studied 9.75 mg alone. With
the exception of 1 mg strength, the trials yielded
statistically significant results on both PANSS
(reductions of 6 and 7, respectively) and CGI-S
[Andrezine et al. 2006; Tran-Johnson et al. 2007].
A third trial devoted to bipolar disorder associated
agitation, using instead lorazepam as comparator,
studied strengths of 9.75 and 15 mg, yielding sta-
tistically significant results, a reduction of 9 com-
pared with placebo [Zimbroff et al. 2007].
Long-acting injectable for schizophrenia. The first
aripiprazole depot preparation to receive FDA
approval involved a 12-week trial comparing
once-monthly 400 mg injections with placebo
using the PANSS, which resulted in a greater
improvement in score over placebo of 15 [Kane
et al. 2014]. In a longer term trial (52 weeks), the
primary measure of efficacy was time to exacerba-
tion of psychotic symptoms/impending relapse
[Kane et al. 2012]. Aripiprazole’s time to relapse
was significantly greater than for placebo. Fur-
ther, scores on the PANSS and CGI-S were sig-
nificantly improved for those given aripiprazole
compared with placebo [Kane et al. 2012].
Aripiprazole lauroxil, another long-acting inject-
able preparation, was studied over 12 weeks in
adults with schizophrenia receiving either 441 or
882 mg, or placebo once monthly [Meltzer et al.
2015]. Statistically significant decreases in the
primary efficacy measure, the PANSS, were
reached with both 441 and 882 mg, by approxi-
mately 11 and 12, respectively. Both dosages also
achieved statistically significant results (either
‘much improved’ or ‘very much improved’) on
the CGI Improvement (CGI-I) scale. Further, all
these results were considered clinically meaning-
ful in reducing psychotic symptoms both in
response to an acute exacerbation and maintained
over the following 12 weeks [Meltzer et al. 2015].
Brexpiprazole
Schizophrenia. Leslie Citrome devoted a system-
atic review entirely to brexpiprazole [Citrome,
2015]. The author outlines two phase III studies
which found statistically significant reductions
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compared with placebo, based again on the
PANSS score for the therapeutic dosages of 2 and
4 mg in one study, and 4 mg in the other [Correll
et al. 2015; Kane et al. 2015]. In the first study, 2
and 4 mg improved PANSS scores compared with
placebo by 9 and 8, respectively [Correll et al.
2015]. The second study found success with 4 mg
and a 6-point greater reduction of PANSS score
[Kane et al. 2015].
Major depressive disorder. For efficacy in control-
ling major depressive disorder as an augmenta-
tion strategy, a pair of 6-week, double-blinded,
placebo-controlled studies compared changes in
MADRS [Thase et al. 2015a, 2015b]. The sub-
jects had previously been treated over 8 weeks
with a standard antidepressant, and those not
responding were then randomized and augmented
with brexpiprazole or placebo.Treatment response
was based on a reduction of at least 50% in
MADRS score. The first study evaluated 1 and
3 mg strengths, and only the 3 mg strength
improved MADRS compared with placebo with
statistical significance [Thase et al. 2015a]. The
second study used 2 mg, which improved MADRS
by three more than placebo (p = 0.0002) [Thase
et al. 2015b].
Cariprazine
Schizophrenia. Cariprazine gained FDA approval
following statistically significant differences in
PANSS scores compared with placebo in three,
6-week trials [Durgam et al. 2014, 2015a, 2015b].
One employed risperidone as an active control
while studying 1.5, 3, and 4.5 mg strengths, with
improvements over placebo of 8, 9, and 10,
respectively [Durgam et al. 2014]. A second study
instead used aripiprazole as active control for
3 mg cariprazine (with an improvement of 6 over
placebo) and 6 mg (better by 9 over placebo)
[Durgam et al. 2015a]. A third study used two
flexible-dose range groups of 3–6 mg and 6–9 mg,
both showing superiority to placebo with least
squares mean differences of 7 for the 3–6 mg dose
range and 10 for the 6–9 mg range [Durgam et al.
2015b].
Bipolar mania. For efficacy treating bipolar
mania, three, 3-week placebo-controlled, double-
blinded trials used the YMRS [Calabrese et al.
2015; Durgam et al. 2015c; Sachs et al. 2015]. All
demonstrated efficacy with doses starting at
3 mg/day. The first study used two flexible-dose
range groups of 3–6 and 6–12 mg/day, each
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JS Frankel and TL Schwartz
resulting in greater scores than placebo by 6
[Calabrese et al. 2015]. A second and a third
study both used dose ranges of 3–12 mg/day, with
improvements over placebo of 6 and 4, respec-
tively [Durgam et al. 2015c; Sachs et al. 2015].
Within this effective range of 3–12 mg/day,
strengths higher than 6 mg were not superior to
lower doses, especially given associations between
dose and adverse effects [Calabrese et al. 2015;
Durgam et al. 2015c; Sachs et al. 2015].
Comparative efficacy
Citrome also recently compared aripiprazole,
brexpiprazole, and cariprazine using number
needed to treat (NNT) statistical analysis
[Citrome, 2005]. His extended work features a
table that concisely compares efficacy, particu-
larly including 95% confidence intervals of the
statistically significant improvements of these
three drugs over placebo. Among schizophrenia
trials, aripiprazole resulted in the greatest reduc-
tion in PANSS (by 12.7 to brexpiprazole’s 8.7
and cariprazine’s 10.4); for bipolar mania,
cariprazine reduced YMRS the most (6.1 to ari-
piprazole’s 5.3); and for adjunctive treatment for
major depression, brexpiprazole showed the
greatest reduction in MADRS (3.2 to aripipra-
zole’s 3.0) [Citrome, 2005]. However, the confi-
dence intervals overlap between drugs for the
same indication and scale, which is suggestive of
comparable efficacy based on the results of these
trials [Citrome, 2005]. While there are no cur-
rent, three-way novel head-to-head comparative
trials, differences found across trials suggest com-
parative efficacy owing to no statistical signifi-
cance. Per FDA standards, it seems that if each
antipsychotic is dosed appropriately it can lower
psychosis in schizophrenia. There are no current
data for cariprazine in treating depressive disor-
der so brexpiprazole and aripiprazole have a dis-
tinct advantage. For treating mania, brexpiprazole
has minimal data, and both aripiprazole and
cariprazine have garnered regulatory approval.
Comparative adverse effects
Aripiprazole
Tables 3–8 list the adverse effects for each agent.
The most common adverse effects for aripiprazole
were headache (27%), agitation (19%), anxiety
(17%), insomnia (16%), akathisia (13%), nausea
(13%), vomiting (11%), constipation (10%), dys-
pepsia (9%), and dizziness (9%).
35
Therapeutic Advances in Psychopharmacology 7(1)
Table 3. Constitutional adverse effects.
Aripiprazole
Fatigue 6% (4%)
Decreased appetite – –
Increased appetite 3% (1%)
Pyrexia – –
Weight increase – 5% (2%)
Placebo rates appear in parentheses.
Table 4. Cardiovascular effects.
Aripiprazole
Hypertension – –
Tachycardia 6% (3%)
orthostasis 4% (3%)
Placebo rates appear in parentheses.
Aripiprazole showed the highest rates of the three
drugs for fatigue, increased appetite (tied with
brexpiprazole), tachycardia, xerostomia, consti-
pation, nausea and vomiting, blurry vision (tied
with cariprazine), dizziness, headache, agitation,
anxiety, insomnia, and restlessness (tied with
cariprazine).
Aripiprazole showed the lowest rate of the three
drugs for EPS (excluding akathisia), dystonia,
Parkinsonism, and abdominal pain.
Brexpiprazole
For brexpiprazole, the 10 most common adverse
effects were headache (9%), agitation (8%),
insomnia (8%), akathisia (7%), EPS excluding
akathisia (6%), sedation (5%), weight increase
(5%), and nausea (4%). Many of these effects are
reduced compared with aripiprazole. Notably,
akathisia is almost 50% less.
Interestingly, brexpiprazole showed the highest
rate of the three drugs for increased appetite (tied
with aripiprazole), and weight increase.
Brexpiprazole showed the lowest rate of the three
drugs for akathisia, fatigue (tied with cariprazine),
constipation, diarrhea, dyspepsia, nausea, dizzi-
ness, headache, and somnolence.
Cariprazine
Cariprazine’s most common adverse reactions
included EPS excluding akathisia (21%),
36
Brexpiprazole Cariprazine
3% (2%) 3% (1%)
3% (1%)
3 (2%) –
1% (1%)
2% (1%)
Brexpiprazole Cariprazine
4% (1%)
– 2% (1%)
– –
Table 5. Dermatologic effects.
Aripiprazole Brexpiprazole Cariprazine
Rash 7% (7%) – 4% (1%)
Placebo rates appear in parentheses.
Parkinsonism (18%), akathisia (14%), insomnia
(8%), constipation (8%), nausea (8%), somno-
lence (7%), dyspepsia (6%), and vomiting (6%).
Compared with the previous two agents, caripra-
zine may have the greatest EPS risk.
Cariprazine showed the highest rate of the three
drugs for EPS (excluding akathisia), Parkinsonism,
akathisia, abdominal pain, somnolence, and
restlessness.
Cariprazine showed the lowest rate of the three
drugs for fatigue (tied with brexpiprazole), weight
gain, tachycardia, xerostomia, vomiting, and
insomnia (tied with brexpiprazole).
Discontinuation rates due to adverse effects
are shown in Table 9. Cariprazine had the
highest rate, followed by aripiprazole, and
then brexpiprazole with the lowest rate. The
most common adverse effect leading to discon-
tinuation for all three atypicals was akathisia.
Among the placebo group, the most common
adverse effects were either worsening psy-
chotic or manic symptoms, presumably due to
nontreatment.
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 JS Frankel and TL Schwartz

Table 6. Gastrointestinal effects.

Aripiprazole Brexpiprazole Cariprazine

Abdominal discomfort/pain 3% (2%) – 5% (5%)
Constipation 10% (6%) 2% (1%) 8% (5%)
Diarrhea 7% (8%) 3% (2%) 4% (3%)
Dry mouth 5% (4%) – 2% (2%)
Dyspepsia 9% (7%) 3% (2%) 6% (5%)
Elevated AST/ALT – 1% (0%)
Nausea 13% (9%) 4% (4%) 8% (6%)
Oropharyngeal pain – – 2% (2%)
Toothache/dentalgia 4% (3%) – 3% (3%)
Vomiting 11% (6%) – 6% (4%)
Placebo rates appear in parentheses.
ALT, alanine transaminase; AST, aspartate transaminase.

Table 7. Neurological effects.

Aripiprazole Brexpiprazole cariprazine

Blurry vision 3% (1%) – 3% (1%)
Dizziness 9% (6%) 3% (1%) 5% (3%)
Extrapyramidal disorders (w/o akathisia) 4% (2%) 6% (3%) 21% (10%)
Akathisia 13% (4%) 7% (3%) 14% (4%)
Dystonia 1% (0%) – 3% (0%)
Parkinsonism 4% (0%) – 18% (8%)
Tremor 5% (3%) 3% (2%) –*
Headache 27% (21%) 9% (9%) 12% (13%)
Inattention 3% (1%) – –
Sedation 7% (4%) 5% (1%) –$
Somnolence 5% (3%) 3% (2%) 7% (5%)
Placebo rates appear in parentheses.
*Tremor was considered a component of Parkinsonism in the cariprazine studies.
$Sedation was considered a component of somnolence in the cariprazine studies.

Table 8. Psychiatric effects.

Aripiprazole Brexpiprazole Cariprazine

Agitation 19% (17%) 8% (9%) –
Anxiety 17% (13%) 2% (1%) –
Insomnia 16% (10%) 8% (7%) 8% (7%)
Restlessness 5% (3%) 2% (0%) 5% (3%)
Placebo rates appear in parentheses.

Table 9. Discontinuation rates due to adverse effects.

Aripiprazole Brexpiprazole Cariprazine

Discontinuation rates 8.8% (7.5%) 5.7% (5.0%) 10.1% (9.4%)
Placebo rates appear in parentheses.

http://tpp.sagepub.com 37
Therapeutic Advances in Psychopharmacology 7(1)
Discussion
This paper has sought to thoroughly review a sub-
class of second-generation antipsychotics that
may be referred to collectively as dopamine stabi-
lizers or dopamine-2/3 receptor partial agonists.
All agents when faced with neurophysiologic
dopamine neuronal hyperactivity in the limbic
system act as net dopamine antagonists and slow
limbic firing, and all diminish psychosis in schizo-
phrenia equally. All can facilitate dopamine activ-
ity in the limbic system or cortex if physiologically
dopamine activity is below normal. This likely is
a procognitive, drive and energy mechanism,
and theoretically could enhance antidepressant
response. Aripiprazole and brexpiprazole are
approved in the area for depression management
and cariprazine is currently being investigated.
For a patient with concurrent depression and psy-
chosis, the selection between aripiprazole and
brexpiprazole may be based on the different
adverse effect profiles, given their comparable
efficacies; the rate of insomnia for brexpiprazole
was half that of aripiprazole, for example, which
could guide therapy for a patient already deprived
of sleep. Cariprazine has recently gained regula-
tory language, suggesting it can improve negative
schizophrenia symptoms which would be a first in
class. It is possible that certain negative symp-
toms can be extrapolated to those experiencing
depressive disorder (amotivation, apathy, lack of
will or drive, etc.) and this drug may be used off
label for depression and ideally will gain regula-
tory approval.
Additionally, all three agents manipulate a variety
of serotonin receptors. The SSRI Plus class of
antidepressants has been recently heralded by the
approval of vilazodone and vortioxetine, which
tout a basic SSRI property plus serotonin 1a
receptor partial agonism (vilazodone/vortioxe-
tine) and 3/7 receptor (vortioxetine) antagonism.
This latter drug has gained regulatory language,
stating it may improve cognition in people with
depression. This is drawing awareness to specific
serotonin receptor modulation in the antidepres-
sant class, but many of the properties are found
in the three dopamine-stabilizing atypical antip-
sychotics discussed here. They all may have
antidepressant effects that are also steeped in
procognitive and procircadian mechanisms.
These are truly multimodal drugs that have
gained disease state indications and approvals
for use but pharmacodynamically may be theo-
retically helpful in improving agitation, aggres-
sion, anxiety, insomnia, fatigue, attention, and
38
concentration regardless of disease state. Future
clinical studies are warranted in these areas.
The authors suggest using these drugs front line
within their approved areas. If an initial agent is
fraught with side effects, then switching to one of
the other three is clearly warranted as side-effect
profiles are subtly different as sedation, weight
gain, and akathisia rates differ. Clinicians may
choose the drug based on side-effect profile. This
approach dates back to the 1950s–1990s and may
be comparable to choosing a high- versus low-
potency first-generation typical antipsychotic. Per
class labeling all three of these agents carry warn-
ings for EPS, TD, metabolic disorder, increased
suicidality in young adults being treated for
depressive disorder, agranulocytosis, and risk of
stroke or cardiac death in those with dementia.
Informed consent and diligent clinical monitoring
is warranted. Off-label use should be docu-
mented, with clinical rationale and perhaps com-
ment about pharmacodynamic theory being used
to guide the choice of drug in the absence of
defined clinical trials in the off-label disease state
area. Finally, if there is a therapeutic failure
despite adequate dosing of one of these three
agents, any of the other agents may be tried as
they all have a subtly unique pharmacodynamic
receptor affinity profile that may offer an advan-
tage to patients on a case-by-case basis.
Acknowledgements
This paper is the sole work of the authors.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
Conflict of interest statement
The authors declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
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