The ABC's of Dopamine Receptor Partial Agonists - Aripiprazole, Brexpiprazole and Cariprazine - The 15-Min Challenge To Sort These Agents Out PDF
The ABC's of Dopamine Receptor Partial Agonists - Aripiprazole, Brexpiprazole and Cariprazine - The 15-Min Challenge To Sort These Agents Out PDF
The ABC's of Dopamine Receptor Partial Agonists - Aripiprazole, Brexpiprazole and Cariprazine - The 15-Min Challenge To Sort These Agents Out PDF
Differences
and similarities
among the
three
dopamine
receptor
partial agonists
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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
Mechanism of action
Contraindications
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Table 1 Continued
Generic name
Aripiprazole
Brexpiprazole
Cariprazine
Not applicable
Plasma half-life
Drug interactions
Most commonly encountered
adverse effects in adults
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Table 2 Pharmacodynamic proles: in vitro binding afnities for human receptors (35, 79)
Aripiprazole
Brexpiprazole
Cariprazine
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.
1.2)
1.4)
(1) 2 mg/day:
(2) 1 mg/day:
3 mg/day:
2.8 ( 4.5,
3.0 ( 4.7,
13.1, 4.4)
12.0, 3.1)
7.2, 1.1)
10.6, 2.4)
Not applicable
(
(
(
(
8.7
7.6
3.1
6.5
(1) 2
4
(2) 2
4
mg/day:
mg/day:
mg/day:
mg/day:
CI, condence interval; MADRS, MontgomeryAsberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale.
Table 3 Acute efcacy in adults in placebo-controlled randomised trials as extracted from product labelling (35)
Not applicable
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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)
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.
3
6
11
25
34
19
8
20
58
3
ND
29
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
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*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
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*
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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
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
0.7
1.4
1.7
1.4
3.1
16
1.5
*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
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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