EXTENDED EDITORIAL

The ABCs of dopamine receptor partial agonists

aripiprazole, brexpiprazole and cariprazine: the 15-min
challenge to sort these agents out
In prior 15-min challenges, we tackled the three new
anorectic agents (1) and three new antidepressant
medications (2). This time we will sort out three dopamine receptor partial agonists, one old (aripiprazole,
commercialised in 2002, and now available as a generic
medication) and two new (brexpiprazole and cariprazine, both commercialised in 2015) that have been
approved for the treatment of schizophrenia as well as
other disorders. How are they similar? How are they
different?
Table 1 is a list of pertinent information regarding
indications, contraindications, bolded boxed warnings, dosage recommendations, drug interactions and
most commonly encountered adverse effects, taken
directly from the product labels for each of these
agents (35).
The approved indications differ. Although all three
are approved for the treatment of schizophrenia,
both aripiprazole and brexpiprazole are also
approved for adjunctive treatment of major depressive disorder, and both aripiprazole and cariprazine
are also approved for acute treatment of manic or
mixed episodes associated with bipolar I disorder. In
addition, aripiprazole is improved for a number of
different disease states in the paediatric population.
Aripiprazole is also available as a short-acting intramuscular injection for the management of agitation
associated with schizophrenia or bipolar mania. A
long-acting injectable formulation of aripiprazole for
the treatment of schizophrenia is also marketed,
using a different product label (6).
Although the mechanisms of action as listed are
similar, the three agents differ in terms of their pharmacodynamic proles (Table 2). Compared with
aripiprazole, brexpiprazole has lower intrinsic activity
at the dopamine D2 receptor and has an approximately 10-fold higher afnity for serotonin 5-HT1A
and 5-HT2A receptors, potentially enhancing tolerability (79). When cariprazine was compared with
aripiprazole in functional assays for dopamine D2
and D3 receptors, similar D2 and higher D3 antagonist-partial agonist afnity and a 3- to 10-fold
greater D3 vs. D2 selectivity was observed for cariprazine (10). As noted in an earlier review (11), whether
targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains
unknown but theoretically dopamine D3 preferring
agents may exert pro-cognitive effects.

2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220.

Contraindications are similar, as are the bolded

boxed warnings as generally found in all antipsychotic drug labels. Additional warnings are included
regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval
for the treatment of major depressive disorder.
Although all three agents are dosed once daily, the
starting dose for brexpiprazole (1 mg/day) is lower
than the recommended dose range of 24 mg/day
for schizophrenia or the recommended dose of
2 mg/day for major depressive disorder. Thus, brexpiprazole will require titration. The recommended
rate of titration depends on the disease state being
treated and for schizophrenia the recommended
titration schedule is to increase to 2 mg/day on Day
5 to Day 7, then to 4 mg/day on Day 8 based on
the patients clinical response and tolerability. For
major depressive disorder, titration of brexpiprazole
is slower, with dosage increases occurring at weekly
intervals. In contrast, the starting dose for aripiprazole can be therapeutic, as can the starting dose for
cariprazine for schizophrenia (1.5 mg/day). For the
treatment of bipolar mania, cariprazine will need to
be titrated from the starting dose of 1.5 mg/day to
the recommended target dose range of 36 mg/day;
this can be done on Day 2. Cariprazine has been
tested in clinical trials at higher doses; however,
doses that exceed 6 mg/day did not confer signicant additional benet (5). Of note, an important
metabolite of cariprazine, didesmethyl cariprazine,
has a half-life of 13 weeks, thus following discontinuation of cariprazine the decline in plasma concentrations of active drug and metabolites will be
slow.
Table 3 outlines the efcacy information from the
pivotal acute short-term trials as extracted from
product labelling (35) for the different indications
(schizophrenia, bipolar mania and adjunctive use in
major depressive disorder). Additional information
can be found in the corresponding published or
presented studies for aripiprazole (1222), brexpiprazole (2326) and cariprazine (2732).
More intuitive than the comparisons of effect size
using placebo-subtracted differences in least mean
squares is the number needed to treat (NNT) vs.
placebo for the outcome of response (33). From the
four positive pivotal short-term acute schizophrenia
trials for aripiprazole in adults (1215), using the

Differences
and similarities
among the
three
dopamine
receptor
partial agonists

1211

1212

Editorials

Table 1 Overview and indications, contraindications, bolded boxed warnings, adult dosage recommendations, drug interactions and most

commonly encountered adverse effects in adults, taken from the highlights of prescribing information and section 12.1 (Mechanism of Action)
from the product label (35)
Generic name

Aripiprazole

Brexpiprazole

Cariprazine

US brand name
Initial US approval
Formulations available

Abilify
2002
Tablets, oral disintegrating tablets, oral
solution, short-acting intramuscular
injection. There is a long-acting
intramuscular injection for
schizophrenia that has its own
product label.
The mechanism of action of
aripiprazole in schizophrenia or
bipolar mania is unknown. However,
the efcacy of aripiprazole could be
mediated through a combination of
partial agonist activity at D2 and 5HT1A receptors and antagonist activity
at 5-HT2A receptors. Actions at
receptors other than D2, 5-HT1A, and
5-HT2A may explain some of the other
clinical effects of aripiprazole (e.g. the
orthostatic hypotension observed with
aripiprazole may be explained by its
antagonist activity at adrenergic a1
receptors).
Treatment of schizophrenia (adults and
paediatrics); as monotherapy or as an
adjunct to lithium or valproate in both
the acute treatment of manic or
mixed episodes associated with
bipolar I disorder (adults and
paediatrics) and the maintenance
treatment of bipolar I disorder
(adults); for the adjunctive treatment
of major depressive disorder (adults);
to treat irritability associated with
autistic disorder (paediatrics); and for
the treatment of Tourettes disorder
(paediatrics). The short-acting injection
(9.75 mg) is indicated for agitation
associated with schizophrenia or
bipolar mania.
History of a hypersensitivity reaction to
aripiprazole. Reactions have ranged
from pruritus/urticaria to anaphylaxis.

Rexulti
2015
Tablets

Vraylar
2015
Capsules

The mechanism of action of

brexpiprazole in the treatment of
major depressive disorder or
schizophrenia is unknown. However,
the efcacy of brexpiprazole may be
mediated through a combination of
partial agonist activity at serotonin
5-HT1A and dopamine D2 receptors,
and antagonist activity at serotonin
5-HT2A receptors.

The mechanism of action of cariprazine in

schizophrenia and bipolar I disorder is
unknown. However, the efcacy of
cariprazine could be mediated through a
combination of partial agonist activity at
central dopamine D2 and serotonin 5-HT1A
receptors and antagonist activity at
serotonin 5-HT2A receptors. Cariprazine
forms two major metabolites, desmethyl
cariprazine and didesmethyl cariprazine
that have in vitro receptor binding proles
similar to the parent drug.

Treatment of schizophrenia (adults);

adjunctive treatment of major
depressive disorder (adults).

Treatment of schizophrenia (adults); acute

treatment of manic or mixed episodes
associated with bipolar I disorder (adults).

Known hypersensitivity to brexpiprazole

or any of its components. Reactions
have included rash, facial swelling,
urticaria and anaphylaxis.

Increased mortality in elderly patients

with dementia related psychosis.
Suicidal thoughts and behaviours.
Starting dose 1015 mg/day,
recommended dose 1015 mg/day,
maximum dose 30 mg/day

Increased mortality in elderly patients

with dementia related psychosis.
Suicidal thoughts and behaviours.
Starting dose 1 mg/day, recommended
dose range 24 mg/day, maximum
dose 4 mg/day

Known hypersensitivity to cariprazine.

Reactions have ranged from rash, pruritus,
urticaria and events suggestive of
angioedema (e.g. swollen tongue, lip
swelling, face oedema, pharyngeal
oedema and swelling face).
Increased mortality in elderly patients with
dementia related psychosis.

Mechanism of action

Indications (with data included

in Section 14. Clinical Studies)

Contraindications

Bolded boxed warnings

Dosage: adults with

schizophrenia

Starting dose 1.5 mg/day, recommended

dose range 1.56 mg/day

2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220

Editorials

1213

Table 1 Continued

Generic name

Aripiprazole

Brexpiprazole

Cariprazine

Dosage: adults with major

depressive disorder

Starting dose 25 mg/day,

recommended dose 510 mg/day,
maximum dose 15 mg/day
Starting dose 15 mg/day (for adjunct to
lithium or valproate start at
1015 mg/day), recommended dose
15 mg/day, maximum dose
30 mg/day
Elimination half-lives are about 75 h
and 94 h for aripiprazole and its
active metabolite dehydro-aripiprazole,
respectively.
CYP2D6 inhibitors, CYP3A4 inhibitors
or inducers
Incidence 5% and at least twice the
rate of placebo: akathisia
(schizophrenia); akathisia, sedation,
restlessness, tremor, and
extrapyramidal disorder (bipolar
mania, monotherapy); akathisia,
insomnia, and extrapyramidal disorder
(bipolar mania, adjunctive therapy);
akathisia, restlessness, insomnia,
constipation, fatigue, and blurred
vision (major depressive disorder);
nausea (short-acting intramuscular
formulation).

Starting dose 0.5 or 1 mg/day,

recommended dose 2 mg/day,
maximum dose 3 mg/day
Not applicable

Not applicable

Dosage: adults with bipolar

mania

Plasma half-life

Drug interactions
Most commonly encountered
adverse effects in adults

denition of response as a 30% or greater decrease in

the Positive and Negative Syndrome Scale (PANSS)
total score or a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2
(much improved), and pooling the data for aripiprazole doses 1030 mg/day, response rates were 38%
for aripiprazole vs. 24% for placebo, resulting in a
NNT of 8 (95% CI 613). Using the identical denition of response, pooling together all the available
data for the recommended target dose of brexpiprazole for schizophrenia (24 mg/day) from the two
studies listed in the product label (23,24), the percentage of responders was 46%, compared with 31%
for the pooled placebo groups, yielding a NNT of 7
(95% CI 512) (34). A more conservative denition
of response was used in the reporting for the cariprazine studies and was simply a 30% or greater decrease
in the PANSS total score and did not include the
option of including persons who scored a 1 or 2 on
the CGI-I. For pooled doses of cariprazine 1.56 mg/
day (2729), the percentage of responders was 31%,
compared with 21% for the pooled placebo groups,
yielding a NNT of 10 (95% CI 718). Although the
magnitude of the NNT effect size is weaker for
2015 John Wiley & Sons Ltd
Int J Clin Pract, November 2015, 69, 11, 12111220

Elimination half-lives of brexpiprazole

and its major metabolite, DM-3411
(inactive), are 91 h and 86 h,
respectively.
CYP2D6 inhibitors, CYP3A4 inhibitors
or inducers
Incidence 4% and at least twice the
rate of placebo: weight increased
(schizophrenia). Incidence 5% and
at least twice the rate of placebo:
weight increased, akathisia (major
depressive disorder).

Starting dose 1.5 mg/day, recommended

dose range 36 mg/day

Half-lives are 24 days for cariprazine, and

approximately 13 weeks for the active
metabolite didesmethyl cariprazine.
CYP3A4 inhibitors or inducers
Incidence 5% and at least twice the rate
of placebo: extrapyramidal symptoms and
akathisia (schizophrenia); extrapyramidal
symptoms, akathisia, dyspepsia, vomiting,
somnolence, and restlessness (bipolar
mania).

cariprazine, the 95% CIs overlap with that for

aripiprazole and brexpiprazole (Figure 1). An
appropriately designed head-to-head trial would be
necessary to directly test non-inferiority.
From the four positive pivotal short-term acute
bipolar mania trials for aripiprazole monotherapy in
adults (1619), using the denition of response as a
50% or greater decrease in the Young Mania Rating
Scale (YMRS) total score, and pooling the data for
aripiprazole doses 1530 mg/day, response rates were
47% for aripiprazole vs. 31% for placebo, resulting
in a NNT of 7 (95% CI 511). Similar results are
observed in the adjunctive aripiprazole acute bipolar
mania trial (20) where the NNT for response was
also 7. Using the identical denition of response,
pooling together all the available data for the recommended target dose of cariprazine for bipolar mania
(36 mg/day) from the three studies listed in product labelling (3032), the percentage of responders
was 57%, compared with 36% for the pooled placebo
groups, yielding a NNT of 5 (95% CI 48). The
magnitude of the NNT effect size is stronger for cariprazine; however, the 95% CI overlaps with that for
aripiprazole.

1214

Editorials

Table 2 Pharmacodynamic proles: in vitro binding afnities for human receptors (35, 79)

Aripiprazole

Brexpiprazole

Cariprazine

Very high binding afnities

(subnanomolar Ki < 1 nM)

Dopamine D2 (0.34 nM)*

Dopamine D3 (0.8 nM)*
Serotonin 5-HT2B (0.36 nM)

Serotonin 5-HT1A (0.12 nM)*

Adrenergic a1B (0.17 nM)
Dopamine D2 (0.30 nM)*
Serotonin 5-HT2A (0.47 nM)
Adrenergic a2C (0.59 nM)

Dopamine D3 (0.085 nM)*

Dopamine D2L (0.49 nM)*
Serotonin 5-HT2B (0.58 nM)
Dopamine D2S (0.69 nM)*

High binding afnities

(Ki values between 1 and 5 nM)

Serotonin 5-HT1A (1.7 nM)*

Serotonin 5-HT2A (3.4 nM)

Dopamine D3 (1.1 nM)*

Serotonin 5-HT2B (1.9 nM)
Adrenergic a1D (2.6 nM)
Serotonin 5-HT7 (3.7 nM)
Adrenergic a1A (3.8 nM)

Serotonin 5-HT1A (2.6 nM)*

Moderate binding afnities

(Ki values between 5 and 100 nM)

Serotonin 5-HT2C (15 nM)

Adrenergic a2C (38 nM)
Serotonin 5-HT7 (39 nM)
Dopamine D4 (44 nM)
Adrenergic a1B (35 nM)
Adrenergic a1A (57 nM)
Histamine H1 (61 nM)
Adrenergic a2A (74 nM)
Serotonin reuptake site (98 nM)

Dopamine D4 (6.3 nM)

Adrenergic a2A (15 nM)
Adrenergic a2B (17 nM)
Histamine H1 (19 nM)
Serotonin 5-HT1B (32 nM)
Serotonin 5-HT2C (34 nM)
Serotonin 5-HT6 (58 nM)
Adrenergic b1 (59 nM)
Adrenergic b2 (67 nM)

Serotonin 5-HT2A (18.8 nM)

Histamine H1 (23.2 nM)

Weak binding afnities

Adrenergic a2B (103 nM)

Adrenergic b1 (141 nM)
Adrenergic b2 (163 nM)
Dopamine D4 (510 nM)
Serotonin 5-HT6 (570 nM)
Serotonin 5-HT1B (830 nM)
Serotonin 5-HT5A (1240 nM)
Dopamine D1 (1960 nM)
Muscarinic M1 (6780 nM)

Serotonin 5-HT5A (140 nM)

Dopamine D1 (160 nM)
Muscarinic M1 (> 1000 nM,
67% inhibition at 10 lM)
Adrenergic b3 (> 10,000 nM)

Serotonin 5-HT7 (111 nM)

Serotonin 5-HT2C (134 nM)
Adrenergic a1A (155 nM)
Muscarinic receptors
(IC50 > 1000 nM)

In case of conicting information for aripiprazole, Ki values taken preferentially from the most current information: product labelling (3), then from (8). *Partial
agonist at these receptors.

From the two positive pivotal short-term acute

major depressive disorder trials for aripiprazole
(21,22), using the denition of response as a 50% or
greater decrease in the MontgomeryAsberg Depression Rating Scale (MADRS) total score, and pooling
the data (aripiprazole exibly dosed 220 mg/day,
with a median dose of 10 mg/day), response rates
were 33% for aripiprazole vs. 20% for placebo,
resulting in a NNT of 8 (95% CI 617). When
including a third trial not described in product labelling (35), the NNT is strengthened to a more robust
7 (95% CI 511). When the results for brexpiprazole
1, 2 and 3 mg from the two pivotal trials are pooled
together (25,26), 23.2% of the patients receiving
brexpiprazole were responders, vs. 14.5% for placebo,
yielding a NNT of 12 (95% CI 826) (34). Inclusion
of the 1.5 mg dose arm and the placebo arm from
the Phase II study for which results are also available

but not included in product labelling, the NNT

becomes a slightly more robust 11 (95% CI 820)
(34). Although the magnitude of the NNT effect size
is stronger for aripiprazole than for brexpiprazole,
the 95% CIs do overlap.
Table 1 includes a summary of the most commonly encountered adverse effects in adults. Table 4
summarises the safety and tolerability information
regarding rate of discontinuation because of adverse
events, and the incidence of the most common
adverse event, together with the calculated number
needed to harm (NNH). Rates of discontinuation
because of an adverse event were not higher for
active medication vs. placebo for the schizophrenia
studies suggesting excellent overall tolerability; however, for the other disease states, NNH vs. placebo
for discontinuation because of an adverse event
ranged from 17 (adjunctive use of aripiprazole for
2015 John Wiley & Sons Ltd
Int J Clin Pract, November 2015, 69, 11, 12111220

 2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220

Four positive short-term (3-week) trials:

1.2)
1.4)

3.2 ( 4.9, 1.5)

1.3 ( 2.7, 0.1)
2.0 ( 3.4, 0.5)

(1) 2 mg/day:
(2) 1 mg/day:
3 mg/day:

2.8 ( 4.5,
3.0 ( 4.7,

Two positive short-term (6-week) trials:

13.1, 4.4)
12.0, 3.1)
7.2, 1.1)
10.6, 2.4)

Two positive short-term (6-week) trials:

Not applicable

(
(
(
(

(1) 520 mg/day:

(2) 520 mg/day:

(1) 3015 mg/day: 5.3 ( 7.9, 2.8)

(2) 3015 mg/day: 4.8 ( 7.8, 1.8)
(3) 1530 mg/day: 3.6 ( 5.8, 1.5)
(4) 1530 mg/day: 2.3 ( 4.4, 0.1)
Adjunctive 6-week study with 1530 mg/day
plus lithium or valproate: 2.6 ( 4.3, 1.0)

8.7
7.6
3.1
6.5

(1) 2
4
(2) 2
4

mg/day:
mg/day:
mg/day:
mg/day:

Two short-term (6-week) trials:

Four positive short-term (4-week and 6-week) trials:

(1) 15 mg/day: 12.6 ( 18.9, 6.2)
30 mg/day: 8.5 ( 14.8, 2.1)
(2) 20 mg/day: 9.6 ( 15.4, 3.8)
30 mg/day: 9.0 ( 14.8, 3.1)
(3) 10 mg/day: 12.7 ( 19.0, 6.4)
15 mg/day: 9.4 ( 15.7, 3.1)
20 mg/day: 12.1 ( 18.5, 5.7)
(4) 2 mg/day: 2.9 ( 8.3, 2.5)
5 mg/day: 5.2 ( 10.7, 0.2)
10 mg/day: 5.9 ( 11.3, 0.6)

Brexpiprazole vs. placebo

CI, condence interval; MADRS, MontgomeryAsberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale.

Major depressive disorder (adjunct); placebo-subtracted differences in

least-squares mean change from baseline (95% CI) on the MADRS

Bipolar mania; placebo-subtracted differences in least-squares

mean change from baseline (95% CI) on the YMRS

Schizophrenia; placebo-subtracted differences in least-squares

mean change from baseline (95% CI) on the PANSS

Aripiprazole vs. placebo

Table 3 Acute efcacy in adults in placebo-controlled randomised trials as extracted from product labelling (35)

Not applicable

(1) 36 mg/day: 6.1 ( 8.4, 3.8)

612 mg/day: 5.9 ( 8.2, 3.6)
(2) 312 mg/day: 6.1 ( 8.9, 3.3)
(3) 312 mg/day: 4.3 ( 6.7, 1.9)

Three short-term (3-week) trials:

(1) 1.5 mg/day: 7.6 ( 11.8, 3.3)

3 mg/day: 8.8 ( 13.1, 4.6)
4.5 mg/day: 10.4 ( 14.6, 6.2)
(2) 3 mg/day: 6.0 ( 10.1, 1.9)
6 mg/day: 8.8 ( 12.9, 4.7)
(3) 36 mg/day: 6.8 ( 11.3, 2.4)
69 mg/day: 9.9 ( 14.5, 5.3)

Three short-term (6-week) trials:

Cariprazine vs. placebo

Editorials
1215

1216

Editorials

Figure 1 Number needed to treat vs. placebo for response in persons with acute schizophrenia in short-term trials*. *Response dened as a 30% or
greater decrease in the Positive and Negative Syndrome Scale total score or a Clinical Global Impressions-Improvement score of 1 (very much
improved) or 2 (much improved) for aripiprazole or brexpiprazole, or a 30% or greater decrease in the Positive and Negative Syndrome Scale total
score for cariprazine

Table 4 Safety and tolerability: proportion of patients who discontinued the clinical trial(s) because of an adverse event and number needed to

harm (NNH) vs. placebo, and incidence of the most commonly encountered adverse events and NNH vs. placebo in acute short-term studies,
from data extracted from product labelling (35)
% of patients
discontinuing because of
an adverse event

Aripiprazole
Schizophrenia
Bipolar mania
Bipolar mania (adjunct)
Major depressive disorder (adjunct)
Brexpiprazole
Schizophrenia
Major depressive disorder (adjunct)
Cariprazine
Schizophrenia (pooled 1.56 mg/day)
Bipolar mania (36 mg/day)

% of patients with the most commonly

encountered adverse event

Active
Medication

Placebo

NNH

Adverse Event

Active
Medication

7%
11%
12%
6%

9%
10%
6%
2%

NA
100
17
25

Akathisia
Akathisia
Akathisia
Akathisia

8%
13%
19%
25%

4%
4%
5%
4%

25
12
8
5

8%
3%

15%
1%

NA
50

Weight increased
Akathisia

4%
9%

2%
2%

50
15

9%
12%

12%
7%

NA
20

Extrapyramidal
Extrapyramidal

17%
26%

8%
12%

12
8

Placebo

NNH

The % of patients discontinuing because of an adverse event is not currently listed in product labelling if rates for the active drug are similar to or lower than with
placebo. For aripiprazole, this information was contained in prior versions of product labelling. For brexpiprazole, the information was taken from a prior review (34).
For cariprazine, data were extracted from four 6-week trials that in addition to the positive trials noted in product labelling (2729), also included a Phase II proofof-concept study (Litman RE, Papadakis K, Bose A, Xie J. Use of cariprazine in the treatment of schizophrenia: a proof-of-concept trial. Poster presentation. American
Psychiatric Association-Institute on Psychiatric Services, Chicago, Illinois, October 25, 2008). CI, condence interval; NA, not applicable as the rate observed with
medication is lower than that observed with placebo; NNH, number needed to harm.

bipolar mania) to 100 (aripiprazole monotherapy for

bipolar mania), representing reasonable overall
tolerability. For the most commonly encountered
adverse event for each medication, the NNH values
ranged from 5 (akathisia for aripiprazole for adjunctive use in major depressive disorder) to 50 (weight
increased for brexpiprazole for schizophrenia). Prag-

matically, NNH values less than 10 are likely to be

more clinically relevant (33). Placing these agents
into perspective within the context of other available
rst-line oral second-generation antipsychotics is
Table 5, outlining the NNH for clinically relevant
weight gain, somnolence and akathisia. For aripiprazole, brexpiprazole and cariprazine for the treatment
2015 John Wiley & Sons Ltd
Int J Clin Pract, November 2015, 69, 11, 12111220

 2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220

3
6

11
25
34

19

8
20
58

3
ND

29

20 (for SCZ and BM)

50
100
13
7 (for SCZ and BM)
10 (for SCZ and BM)
7
15
42
16
17
11
22
52
ND

21
17
34
18 (for SCZ and BM)
6 (for SCZ and BM)
6
22
16
35
10
35
67
Aripiprazole
Brexpiprazole
Cariprazine (to 6 mg/d)
Risperidone
Olanzapine
Quetiapine IR
Quetiapine XR
Ziprasidone
Paliperidone
Iloperidone
Asenapine
Lurasidone

1217

*Adapted and updated from (34) and Citrome L. A review of the pharmacology, efcacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs
2013; 27: 879911. Data for risperidone are for doses 8 mg/day. For adjunctive use for MDD, data for olanzapine are for the combination of olanzapine with uoxetine. Data for somnolence for aripiprazole for
schizophrenia and bipolar mania are taken from the section regarding potential for cognitive and motor impairment and include sedation. Data for somnolence for brexpiprazole and cariprazine (includes all doses
tested) are taken from the section regarding potential for cognitive and motor impairment and include sedation and hypersomnia. BM, bipolar mania; IR, immediate release; MDD, major depressive disorder; NA,
not available, presumably because the incidence did not meet the reporting threshold; ND, no difference or rate with medication is lower than rate with placebo; NNH, number needed to harm; SCZ, schizophrenia;
XR, extended release.

50

91

167

7
17
NA
ND
143
20

5
15
12

25
112
15
15
25
ND
188
100
39
ND
34
10
50
34

Adjunctive
for MDD
Bipolar
mania
Schizophrenia
Schizophrenia
Antipsychotic

Bipolar
mania

Adjunctive
for MDD

Schizophrenia

Bipolar
mania

Adjunctive
for MDD

NNH for akathisia adverse events

NNH for somnolence adverse events
NNH for weight gain 7%

of schizophrenia, none of the NNH values for weight

gain, somnolence or akathisia were < 10; however,
this was not the case for the mood disorders, where
in general, akathisia was more frequently observed
for each of the agents. For the indication of
schizophrenia, the rank order for propensity for
weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence
aripiprazole > brexpiprazole > cariprazine and the
propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect
comparison and appropriately designed head-to-head
clinical trials will be necessary to accurately assess
these potential differences.
As we compare and contrast, the concept of likelihood to be helped or harmed (LHH) can be helpful,
provided that you select a relevant harm to contrast
with the expected benet (33). Table 6 provides the
NNT for response, NNH for discontinuation because
of an adverse event (where applicable), the NNHs
for weight gain 7%, somnolence adverse events
and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of
aripiprazole for the treatment of major depressive
disorder when comparing response vs. akathisia, all
LHH values are > 1.0 and thus the benet (response)
would be encountered more often than the harm.
When LHH values are 10, this can be interpreted
that one would encounter a response at least 10
times more often than the adverse event of interest.
This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs.
akathisia, for cariprazine for schizophrenia when
comparing response vs. somnolence, and for aripiprazole for bipolar mania when comparing response
vs. discontinuation because of an adverse event.
Additional work has been done with both
brexpiprazole and cariprazine for the maintenance
treatment of schizophrenia (36,37). In addition,
cariprazine has been directly compared with risperidone in a 26-week double-blind study in patients
with schizophrenia with predominant negative
symptoms (38). Cariprazine is also in Phase III of
clinical development for the adjunctive treatment of
major depressive disorder (NCT01838876, NCT0
1715805). Brexpiprazole is also in Phase III of clinical development for the treatment of posttraumatic
stress disorder and for agitation associated with
dementia of the Alzheimers type (39).
There are several important caveats. The harms
discussed are primarily from acute studies and do
not reect effects that can take time to become
manifest, such as tardive dyskinesia, the long-term
accumulation of body weight, or the development of
insulin resistance/type 2 diabetes mellitus (40). The

Table 5 Number needed to harm at a glance: number needed to harm vs. placebo for approved rst-line oral second-generation antipsychotics in adults for weight gain, somnolence and
akathisia, observed in acute short-term studies for schizophrenia, bipolar mania, or major depressive disorder, all doses pooled, as calculated from product labelling*

Editorials

ND
ND
ND
100
20
25
50

8
7
10

7
5

7
11

3.6
4.5

14
4

NA
NA
NA

LHH for
response vs.
discontinuation
because of an
adverse event

22
52

ND
ND

21
17
34

NNH for weight

gain 7%

3.1
4.7

NA
NA

2.6
2.4
3.4

LHH for
response vs.
weight gain 7%

50
34

20
25

20
50
100

NNH for
somnolence
adverse events

7.1
3.1

2.9
5

2.5
7.1
10

LHH for
response vs.
somnolence
adverse events

5
15

12
7

25
112
15

NNH for akathisia

adverse events

0.7
1.4

1.7
1.4

3.1
16
1.5

LHH for response

vs. akathisia
adverse events

*Response for schizophrenia dened as a 30% or greater decrease in the Positive and Negative Syndrome Scale total score or a Clinical Global Impressions-Improvement score of 1 (very much improved) or 2
(much improved) for aripiprazole or brexpiprazole, or a 30% or greater decrease in the Positive and Negative Syndrome Scale total score for cariprazine; response for bipolar mania or major depressive disorder
dened as a 50% or greater reduction in the Young Mania Rating Scale or MontgomeryAsberg Depression Rating Scale, respectively. LHH, likelihood to be helped or harmed; NA, LHH not interpretable because
the rate of the harm observed with medication is lower than that observed with placebo; ND, no difference or rate with medication is lower than rate with placebo; NNH, number needed to harm; NNT, number
needed to treat.

Schizophrenia
Aripiprazole
Brexpiprazole
Cariprazine (to 6 mg/day)
Bipolar mania
Aripiprazole
Cariprazine (to 6 mg/day)
Major depressive disorder
Aripiprazole
Brexpiprazole

Disease state/medication

NNT for
response*

NNH for
discontinuation
because of an
adverse event

Table 6 Likelihood to be helped or harmed: response vs. discontinuation because of an adverse event, and response vs. weight gain 7%, somnolence adverse events or akathisia adverse

events

1218
Editorials

2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220

Editorials

data presented are from carefully conducted

registration trials that enrolled subjects who fullled
restrictive inclusion/exclusion criteria. Such patients
may differ from persons encountered in routine
clinical practice. Thus, pragmatic clinical trials that
are more generalisable will help place these antipsychotic medications into clinical perspective for their
use in the real world. However, schizophrenia,
bipolar disorder and major depressive disorder are

References
1 Citrome L. Lorcaserin, phentermine topiramate
combination, and naltrexone bupropion combination for weight loss: the 15-min challenge to
sort these agents out. Int J Clin Pract 2014; 68:
14015.
2 Citrome L. Vilazodone, levomilnacipran and vortioxetine for major depressive disorder: the 15-min
challenge to sort these agents out. Int J Clin Pract
2015; 69: 1515.
3 Otsuka. ABILIFY (Aripiprazole) Tablets, ABILIFY
DISCMELT (Aripiprazole) Orally Disintegrating
Tablets, ABILIFY (Aripiprazole) Oral Solution,
ABILIFY (Aripiprazole) Injection for Intramuscular use Only. Prescribing Information, Revised
December
2014.
http://www.otsuka-us.com/
Documents/Abilify.PI.pdf (accessed 7 September
2015).
4 Otsuka. REXULTI (Brexpiprazole) Tablets, for Oral
use. Prescribing Information, Revised July 2015.
http://www.otsuka-us.com/Products/Documents/
Rexulti.PI.pdf (accessed 7 September 2015).
5 Actavis. VRAYLAR (Cariprazine) Capsules, for Oral
use. Prescribing Information, Revised September
2015.
http://pi.actavis.com/data_stream.asp?product_group=2028&p=pi (accessed 20 September
2015).
6 Otsuka. ABILIFY MAINTENA (Aripiprazole) for
Extended-Release Injectable Suspension, for Intramuscular use. Prescribing Information, Revised July
2015.
http://www.otsuka-us.com/Products/Documents/Abilify.M.PI.pdf. (accessed 20 September
2015).
7 Citrome L, Stensbl TB, Maeda K. The preclinical
prole of brexpiprazole: what is its clinical
relevance for the treatment of psychiatric disorders?
Expert Rev Neurother 2015 15: 121929.
8 Shapiro DA, Renock S, Arrington E et al. Aripiprazole, a novel atypical antipsychotic drug with a
unique and robust pharmacology. Neuropsychopharmacology 2003; 28: 140011.
9 Maeda K, Sugino H, Akazawa H et al. Brexpiprazole I: in vitro and in vivo characterization of a
novel serotonin-dopamine activity modulator. J
Pharmacol Exp Ther 2014; 350: 589604.
10 Kiss B, Horvath A, Nemethy Z et al. Cariprazine
(RGH-188), a dopamine D(3) receptor-preferring,
D(3)/D(2) dopamine receptor antagonist-partial
agonist antipsychotic candidate: in vitro and neurochemical prole. J Pharmacol Exp Ther 2010; 333:
32840.
11 Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical
efcacy, safety, and tolerability. Expert Opin Drug
Metab Toxicol 2013; 9: 193206.

2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220

1219

heterogeneous disorders and medication response

(and tolerability) in an individual patient can vary.
As always, having additional choices can offer greater
opportunities for success.
L. Citrome
New York Medical College, Valhalla, NY, USA
Email: [email protected]

12 Kane JM, Carson WH, Saha AR et al. Efcacy

and safety of aripiprazole and haloperidol versus
placebo in patients with schizophrenia and
schizoaffective disorder. J Clin Psychiatry 2002;
63: 76371.
13 Potkin SG, Saha AR, Kujawa MJ et al. Aripiprazole,
an antipsychotic with a novel mechanism of action,
and risperidone vs placebo in patients with
schizophrenia and schizoaffective disorder. Arch
Gen Psychiatry 2003; 60: 68190.
14 McEvoy JP, Daniel DG, Carson WH Jr, McQuade
RD, Marcus RN. A randomized, double-blind,
placebo-controlled, study of the efcacy and safety
of aripiprazole 10, 15 or 20 mg/day for the
treatment of patients with acute exacerbations of
schizophrenia. J Psychiatr Res 2007; 41:
895905.
15 Cutler AJ, Marcus RN, Hardy SA, ODonnell A,
Carson WH, McQuade RD. The efcacy and safety
of lower doses of aripiprazole for the treatment of
patients with acute exacerbation of schizophrenia.
CNS Spectr 2006; 11: 691702.
16 Sachs G, Sanchez R, Marcus R et al. Aripiprazole
in the treatment of acute manic or mixed episodes
in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol 2006; 20:
53646.
17 Keck PE Jr, Marcus R, Tourkodimitris S et al. A
placebo-controlled, double-blind study of the efcacy and safety of aripiprazole in patients with
acute bipolar mania. Am J Psychiatry 2003; 160:
16518.
18 Keck PE, Orsulak PJ, Cutler AJ et al. Aripiprazole
monotherapy in the treatment of acute bipolar I
mania: a randomized, double-blind, placebo- and
lithium-controlled study. J Affect Disord 2009; 112:
3649.
19 Young AH, Oren DA, Lowy A et al. Aripiprazole
monotherapy in acute mania: 12-week randomised
placebo- and haloperidol-controlled study. Br J
Psychiatry 2009; 194: 408.
20 Vieta E, Tjoen C, McQuade RD et al. Efcacy of
adjunctive aripiprazole to either valproate or
lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. Am J Psychiatry 2008; 165:
131625.
21 Marcus RN, McQuade RD, Carson WH et al. The
efcacy and safety of aripiprazole as adjunctive
therapy in major depressive disorder: a second
multicenter, randomized, double-blind, placebocontrolled study. J Clin Psychopharmacol 2008; 28:
15665.
22 Berman RM, Marcus RN, Swanink R et al. The
efcacy and safety of aripiprazole as adjunctive

23

24

25

26

27

28

29

30

31

32

therapy in major depressive disorder: a multicenter,

randomized,
double-blind,
placebo-controlled
study. J Clin Psychiatry 2007; 68: 84353.
Correll CU, Skuban A, Ouyang J et al. Efcacy and
safety of brexpiprazole for the treatment of acute
schizophrenia: a 6-week randomized, double-blind,
placebo-controlled trial. Am J Psychiatry 2015; 172:
87080.
Kane JM, Skuban A, Ouyang J et al. A multicenter,
randomized, double-blind, controlled phase 3 trial
of xed-dose brexpiprazole for the treatment of
adults with acute schizophrenia. Schizophr Res
2015; 164: 12735.
Thase ME, Youakim JM, Skuban A et al. Efcacy
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
2015; 76: 122431.
Thase ME, Youakim JM, Skuban A et al. 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 2015 76:
123240.
Durgam S, Starace A, Li D et al. An evaluation of
the safety and efcacy of cariprazine in patients
with acute exacerbation of schizophrenia: a phase
II, randomized clinical trial. Schizophr Res 2014;
152: 4507.
Cutler AJ, Mokliatchouk O, Laszlovszky I, Migliore
R, Durgam S. Cariprazine in Acute Exacerbation of
Schizophrenia: A Fixed-Dose Phase III, Randomized, Double-Blind, Placebo- and Active-Controlled
Trial. Poster Presentation NR10-12. 168th Annual
Meeting of the American Psychiatric Association,
San Francisco, California, May 1822, 2013.
Kane JM, Zukin S, Wang Y et al. Efcacy and
safety of cariprazine in acute exacerbation of
schizophrenia: results from an international, phase
III clinical trial. J Clin Psychopharmacol 2015; 35:
36773.
Calabrese JR, Keck PE Jr, Starace A et al. Efcacy
and safety of low- and high-dose cariprazine in
acute and mixed mania associated with bipolar I
disorder: a double-blind, placebo-controlled study.
J Clin Psychiatry 2015; 76: 28492.
Durgam S, Starace A, Li D et al. The efcacy and
tolerability of cariprazine in acute mania associated
with bipolar I disorder: a phase II trial. Bipolar
Disord 2015; 17: 6375.
Sachs GS, Greenberg WM, Starace A et al. Cariprazine in the treatment of acute mania in bipolar I
disorder: a double-blind, placebo-controlled, phase
III trial. J Affect Disord 2015; 174: 296302.

1220

Editorials

33 Citrome L, Ketter TA. When does a difference

make a difference? Interpretation of number
needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract
2013; 67: 40711.
34 Citrome L. Brexpiprazole for schizophrenia and as
adjunct for major depressive disorder: a systematic
review of the efcacy and safety prole 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
2015; 69: 97897.
35 Berman RM, Fava M, Thase ME et al. Aripiprazole
augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with
inadequate response to antidepressants. CNS Spectr
2009; 14: 197206.
36 Hobart M, Ouyang J, Forbes A et al. Efcacy
and Safety of Brexpiprazole (OPC-34712) as
Maintenance
Treatment
in
Adults
With
Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study. Poster Presentation. American Society of Clinical Psychopharmacology
Annual Meeting, Miami, Florida, June 2225,
2015.

37 Durgam S, Earley W, Li R et al. Long-Term

Cariprazine Treatment for the Prevention of
Relapse in Patients With Schizophrenia: A DoubleBlind, Placebo-Controlled Trial. Poster Presentation. 28th Congress of the European College of
Neuropsychopharmacology,
Amsterdam,
the
Netherlands, August 29September 1, 2015.
38 Debelle M, Nemeth G, Szalai E et al. Cariprazine
as Monotherapy for the Treatment of Schizophrenia Patients With Predominant Negative Symptoms: A Double-Blind, Active Controlled Trial.
Poster Presentation. 28th Congress of the
European College of Neuropsychopharmacology,
Amsterdam, Netherlands, August 29September 1,
2015.
39 Citrome L. Brexpiprazole: a new dopamine D2
receptor partial agonist for the treatment of
schizophrenia and major depressive disorder. Drugs
Today (Barc) 2015; 51: 397414.
40 Citrome L, Kantrowitz J. Antipsychotics for the
treatment of schizophrenia: likelihood to be helped
or harmed, understanding proximal and distal
benets and risks. Expert Rev Neurother 2008; 8:
107991.

Acknowledgements
The author thanks Joshua Kantrowitz and Jamie Karagianis, Editorial Board Members for the International
Journal of Clinical Practice, for their helpful review
and suggestions.

Disclosures
No external funding or writing assistance was utilised in
the production of this extended editorial. Although the
average clinician may take 1530 min to read the editorial and accompanying tables, the creation of this minireview took well in excess of 40 h. In the past 36 months,
Leslie Citrome has engaged in collaborative research
with, or received consulting or speaking fees, from:
Alexza, Alkermes, Allergan, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum,
Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation,
Mylan, Novartis, Noven, Otsuka, Pzer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant.
doi: 10.1111/ijcp.12752

2015 John Wiley & Sons Ltd

Int J Clin Pract, November 2015, 69, 11, 12111220