CNS Drugs (2017) 31:513–525

DOI 10.1007/s40263-017-0442-z

ADIS DRUG EVALUATION

Cariprazine: A Review in Schizophrenia

Karly P. Garnock-Jones1

Published online: 30 May 2017

Ó Springer International Publishing Switzerland 2017

Abstract Cariprazine (VraylarTM) is a dopamine D3-pre- events being of mild to moderate severity, and metabolic
ferring D2/D3 receptor partial agonist indicated for the changes observed were considered generally not clinically
treatment of patients with schizophrenia. This narrative significant. Cariprazine is a useful addition to the treatment
review summarizes pharmacological, efficacy and tolera- options for schizophrenia, and may be of particular use in
bility data relevant to the use of cariprazine in patients with patients with predominantly negative symptoms.
this disorder. In 6-week, phase IIb and III trials in patients
with schizophrenia, cariprazine was significantly more
efficacious than placebo in improving schizophrenia
Cariprazine: clinical considerations in schizophre-
symptoms, including improvements in Positive and Nega-
nia
tive Syndrome Scale (PANSS) total scores. It was associ-
ated with a significantly longer time to relapse than placebo
Dopamine D3-preferring D2/D3 receptor partial
in a long-term, phase III, relapse-prevention study. Car-
agonist
iprazine was also significantly more efficacious than
risperidone in improving PANSS Factor Score for Negative Significantly improves symptoms of schizophrenia,
Symptoms in a phase III trial in patients with predomi- including PANSS total score, in short-term trials
nantly negative symptoms of schizophrenia, a typically Significantly delays schizophrenia relapse with
difficult to treat group of patients. Cariprazine was gener- longer-term treatment
ally well tolerated in clinical trials, with most adverse
Significantly more efficacious than risperidone at
improving PANSS Factor Score for Negative
The manuscript was reviewed by: E. Brandl, Department of Symptoms in patients with predominantly negative
Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin,
Berlin, Germany; J. M. Davis, Department of Psychiatry, University
symptoms of schizophrenia
of Illinois at Chicago, Chicago, IL, USA; M. C. Mauri, Department of Generally well tolerated, with most adverse events
Neuroscience and Mental Health, IRCCS Ospedale Maggiore
Policlinico, Milan, Italy; H. A. Nasrallah, Department of Psychiatry being of mild to moderate severity; the most
and Behavioural Neuroscience, Saint Louis University School of common being extrapyramidal symptoms
Medicine, St Louis, MO, USA; M. H. Rapaport, Department of
Psychiatry and Behavioural Sciences, Emory University School of
Medicine, Atlanta, GA, USA; G. Sani, NESMOS Department,
Sapienza University, Rome, Italy; J. Volavka, Department of
Psychiatry, New York University School of Medicine, Big Sky, MT,
1 Introduction
USA.
Schizophrenia is a psychiatric brain disorder characterized
& Karly P. Garnock-Jones by multiple symptom domains, including positive symp-
demail@springer.com
toms (e.g. hallucinations, delusions), negative symptoms
1
Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, (e.g. emotional apathy, lack of drive), and cognitive deficits
New Zealand (e.g. impaired memory) [1–3]. Negative symptoms can be
514
further divided into primary (deficit) and secondary (re-
lated to positive symptoms and other factors) negative
symptoms [4]. No single symptom is characteristic of
schizophrenia; patients vary widely with regard to the
symptoms that manifest [1, 3]. Schizophrenia is also
recurrent and progressive, and may change with time, with
different symptoms becoming the predominant symptoms
at different times [3].
While available antipsychotics are largely effective with
regard to positive symptoms, most have limited efficacy
with regard to negative symptoms [4]; some have modest
efficacy in secondary negative symptoms, but these
improvements often occur along with improvements in
positive, depressive or extrapyramidal symptoms [5].
Studies specifically investigating the efficacy of antipsy-
chotic drugs in primary negative symptoms are lacking;
thus, confounding factors can potentially mask any con-
clusions that could be made with regard to efficacy in
primary negative symptoms [4]. Negative symptoms often
persist during periods of clinical stability, and can be
severe enough to impair the day-to-day life of patients [5].
As a result, both the European Medicines Agency and the
US FDA have endorsed the specific investigation of neg-
ative symptoms in antipsychotic drug development [5].
Cariprazine (VraylarTM) is a dopamine D3-preferring D2/
D3 receptor partial agonist indicated for the treatment of
patients with schizophrenia in the USA [6]. While the role
of the D3 receptor in schizophrenia is currently unknown,
there is some evidence that D3 receptor blockade could have
pro-cognitive and antidepressant effects, as well as potential
effects on negative symptoms of schizophrenia [7]. This
narrative review summarizes pharmacological, efficacy and
tolerability data relevant to the use of cariprazine in patients
with schizophrenia. The use of cariprazine in patients with
manic or mixed episodes associated with bipolar I disorder,
for which it is also approved in the USA [6], is beyond the
scope of this review.
2 Pharmacodynamic Properties of Cariprazine
While the precise mechanism of action for cariprazine in
patients with schizophrenia is unknown, its effects appear
to occur via its partial agonist activity at central dopamine
D2 and serotonin 5-HT1A receptors and antagonist activity
at 5-HT2A receptors [6]. Cariprazine also acts as a partial
agonist at the D3 receptor and as an antagonist at the
5-HT2B receptor. In vitro studies showed that its highest
binding affinity is for the D3 receptor; it also has high
affinity for the D2, 5-HT1A and 5-HT2B receptors, moderate
affinity for the 5-HT2A and histamine H1 receptors, low
affinity for the 5-HT2C and a1A-adrenergic receptors, and
no appreciable affinity for cholinergic muscarinic receptors
K. P. Garnock-Jones
[6, 8]. Cariprazine has two major metabolites: desmethyl
cariprazine and didesmethyl cariprazine (Sect. 3). These
metabolites have similar binding profiles to that of car-
iprazine, according to in vitro studies [6, 9].
A PET receptor occupancy study in patients with
schizophrenia confirmed that cariprazine is a D3-preferring
partial agonist of both D2 and D3 dopamine receptors [10].
While high dosages (12 mg/day) of cariprazine corresponded
to near-complete occupancy at both receptors after 15 days’
treatment (99 and 95% at D3 and D2), lower dosages
(1 mg/day) corresponded to &1.7-fold greater occupancy at
D3 receptors than D2 (76 and 45%). At an intermediate dosage
(3 mg/day, within the therapeutic dosage range), the mean
receptor occupancy was 92 and 79%, respectively.
Compared with aripiprazole, cariprazine has similar
affinity for the D2 receptor and greater affinity for the D3
receptor, and demonstrates 3- to 10-fold greater selectivity
than aripiprazole for D3 over D2, in vitro [8].
Long-term treatment with cariprazine in rats was asso-
ciated with increased D2 [11, 12] and D4 [11] receptor
levels in the brain, similar to that observed with other
antipsychotics; however, cariprazine was also uniquely
associated with increased D3 receptor levels [11, 12]. No
differences from baseline in D1 receptor levels were
observed with cariprazine treatment [11]. Long-term car-
iprazine treatment in rats was also associated with
increased levels of 5-HT1A and AMPA receptors and
decreased levels of NMDA receptors; these results were
similar to those observed with aripiprazole [12]. Some
preclinical evidence suggests that agonist activity at the
5-HT1A receptor is associated with beneficial effects on
negative symptoms and cognitive dysfunction [13].
In rodent [14–17] and nonhuman primate [18] models of
schizophrenia, cariprazine was associated with antipsy-
chotic-like effects (on both positive and negative symp-
toms) [15–17] and improved performance on cognitive
tasks [14–18]. Cognitive improvements with cariprazine
were not evident in D3-receptor knockout mouse
schizophrenia models, indicating that D3 receptors may
contribute to these effects [14].
At supratherapeutic doses (three times the maximum
recommended dose), cariprazine was not associated with a
clinically relevant prolonged corrected QT interval [6].
3 Pharmacokinetic Properties of Cariprazine
The pharmacokinetics of oral cariprazine can be described
by a three-compartment model, with first-order absorption
and elimination, according to a population pharmacoki-
netic analysis; those of its major metabolites (desmethyl
cariprazine and didesmethyl cariprazine) can be described
by a two-compartment model with linear elimination [19].
Cariprazine: A Review
Following a single dose of cariprazine, the peak plasma
concentration is reached within 3–6 h [6]. With multiple
doses, plasma exposure of cariprazine and its major metabo-
lites increases in an approximately dose-proportional manner.
Steady state is reached at around week 1–2 for cariprazine and
desmethyl cariprazine and around week 4–8 for didesmethyl
cariprazine [6, 20]. The time to steady state for didesmethyl
cariprazine was variable between patients; some had not
reached steady state after 12 weeks’ treatment. At the end of
the 12-week treatment period, mean concentrations of des-
methyl cariprazine and didesmethyl cariprazine were &30
and &400% of cariprazine concentrations.
A high-fat meal had no significant effect on cariprazine
or desmethyl cariprazine exposure, following a single dose
of cariprazine 1.5 mg [6]. Both cariprazine and its major
metabolites are highly plasma-protein bound (91–97%).
Cariprazine undergoes extensive metabolism by CYP3A4
(and CYP2D6 to a lesser extent), producing desmethyl car-
iprazine and didesmethyl cariprazine [6]. CYP3A4 and
CYP2D6 are also responsible for metabolizing desmethyl
cariprazine to didesmethyl cariprazine, which is then metab-
olized to a hydroxylated metabolite by CYP3A4. A population
pharmacokinetic analysis predicted that didesmethyl car-
iprazine was the most common moiety (64.2% of total car-
iprazine); cariprazine and desmethyl cariprazine made up 28.1
and 7.7% of total cariprazine, respectively [19].
Following multiple doses of cariprazine 12.5 mg/day
over 27 days in patients with schizophrenia, &21% of the
daily dose was excreted in the urine (1.2% as unchanged
cariprazine) [6].
Once cariprazine treatment is discontinued, plasma con-
centrations of cariprazine, desmethyl cariprazine and dides-
methyl cariprazine decline in a multi-exponential fashion [6].
Mean cariprazine and desmethyl cariprazine concentrations
drop by 50% in &1 day and by &90% within 1 week; mean
didesmethyl cariprazine concentrations drop by &50% in
1 week and by &90% within &4 weeks [6, 20]. Didesmethyl
cariprazine remained detectable 8 weeks after a single dose of
cariprazine 1 mg [6]. The terminal half-life of cariprazine is
31.6–68.4 h, of desmethyl cariprazine is 29.7–37.5 h, and of
didesmethyl cariprazine is 314–446 h, in patients with
schizophrenia [20].
Patients with mild or moderate hepatic impairment
(Child-Pugh score of 5–9) had a &25% higher exposure to
cariprazine and &45% lower exposure to its major
metabolites than healthy volunteers, following both a sin-
gle dose of cariprazine 1 mg and multiple doses of car-
iprazine 0.5 mg/day for 14 days [6]. No dosage adjustment
is recommended for patients with mild or moderate hepatic
impairment; however, as cariprazine has not been investi-
gated in patients with severe hepatic impairment (Child-
Pugh score of 10–15), use of cariprazine is not recom-
mended in these patients.
515
As cariprazine and its major metabolites are minimally
excreted in urine, and pharmacokinetic analyses did not
show a significant relationship between cariprazine plasma
clearance and creatinine clearance, no dosage adjustment is
required for patients with mild to moderate renal impair-
ment (creatinine clearance C30 mL/min) [6]. However, as
cariprazine has not been investigated in patients with sev-
ere renal impairment (creatinine clearance \30 mL/min),
use of cariprazine is not recommended in these patients.
Cariprazine, desmethyl cariprazine and didesmethyl
cariprazine pharmacokinetics are not affected to a clini-
cally relevant degree by CYP2D6 poor metabolizer status,
age, weight, sex or race [6, 19].
Cariprazine and its major metabolites are not inducers of
CYP1A2 or CYP3A4, according to in vitro studies [6].
They are weak inhibitors of CYP1A2, CYP2C9, CYP2D6
and CYP3A4 and either poor or non-inhibitors of
OATP1B1, OATP1B3, BCRP, OCT2, OAT1 and OAT3;
cariprazine is also a weak inhibitor of CYP2C19, CYP2A6
and CYP2E1. Cariprazine is not likely to cause significant
pharmacokinetic interactions with substrates of these
enzymes and transporters. Its major metabolites are poor or
non-inhibitors of P-glycoprotein, although cariprazine is
likely to be an inhibitor of this transporter. Cariprazine and
its major metabolites are not substrates of P-glycoprotein,
OATP1B1, OATP1B3 or BCRP.
When cariprazine 0.5 mg/day and ketoconazole
400 mg/day (a strong CYP3A4 inhibitor) were coadmin-
istered, cariprazine area under the concentration curve
from time 0 to 24 h (AUC24) increased &4-fold, dides-
methyl cariprazine AUC24 increased &1.5-fold and des-
methyl cariprazine AUC24 decreased by approximately
one-third [6]. Dosage reduction of cariprazine is recom-
mended if coadministered with a strong CYP3A4 inhibitor
(e.g. ketoconazole, clarithromycin, ritonavir). Coadminis-
tration of cariprazine and a CYP3A4 inducer (e.g. rifampin,
carbamezipine) is not recommended [6].
A population exposure-response analysis found that an
increase in efficacy occurred with increasing dosage in the
range of cariprazine 1.5–12 mg/day in patients with
schizophrenia; however, there was a trade-off between the
increased efficacy and an increase in the incidence of
adverse events with increasing dosage [21]. These results
support the FDA-approved dosage range of 1.5–6 mg/day
for the treatment of schizophrenia (Sect. 6).
4 Therapeutic Efficacy of Cariprazine
In an initial 6-week, randomized, double-blind, proof-of-
concept, dose-ranging study of cariprazine in patients with
schizophrenia (n = 392), no significant difference was
found in an overall comparison between cariprazine
516
1.5–4.5 mg/day, cariprazine 6–12 mg/day and placebo in
change from baseline in Positive and Negative Syndrome
Scale (PANSS) total score (primary endpoint); however,
other efficacy endpoints indicated the need for further
investigation [22]. The proof-of-concept study is not fur-
ther discussed.
Thus, the efficacy of cariprazine in patients with
schizophrenia was investigated in three further 6-week,
randomized, double-blind, placebo- [23–25] and active-
controlled [23, 24], multinational, phase IIb [23] and III
[24, 25] studies, a 6-month, randomized, double-blind,
risperidone-controlled, multinational, phase III study in
patients with predominant negative symptoms [5]
(Sect. 4.1), and a B72-week, randomized, double-blind,
placebo-controlled, multinational, relapse-prevention study
[26] (Sect. 4.2).
In the 6-week studies, patients aged 18–60 years were
included if they met DSM-IV-TR criteria for schizophre-
nia, had been diagnosed C1 year ago, had a current exac-
erbation of \2 weeks’ duration, and had experienced
C1 psychotic episode requiring hospitalization or antipsy-
chotic medication change (or intervention [23]) in the past
year [23–25]. Further inclusion criteria were a PANSS
score of 80–120, a score of C4 on at least two of the
PANSS positive symptoms delusions, hallucinatory beha-
viour, conceptual disorganization and suspiciousness/per-
secution, and a Clinical Global Impression-Severity (CGI-
S) score of C4. Patients were excluded if they were
experiencing a first episode of psychosis, or had treatment-
resistant schizophrenia, suicidal or homicidal attempt/in-
tent within the past 2 years, alcohol/substance abuse/de-
pendence within the past 3 months, or various other DSM-
IV-TR disorders [23–25].
Following a B7-day washout period, patients were
randomized to 6 weeks’ treatment with cariprazine 1.5
[23], 3 [23, 24], 4.5 [23], 6 [24], 3–6 [25] or 6–9 mg/day
[25], risperidone 4.0 mg/day [23], aripiprazole 10 mg/day
[24] or placebo [23–25]. Cariprazine dosages [6 mg/day
are not recommended by the US prescribing information
(Sect. 6) [6]. Cariprazine [23–25] and risperidone [23]
were titrated to the target dosage; aripiprazole was initiated
at the target dosage [24]. In the variable-dosage study [25],
patients received fixed dosages from the end of week 3.
Patients were hospitalized from screening to at least
day 28, when discharge was permitted if the patient fit
certain criteria [23–25]. The mean duration of treatment
ranged from 30.5 to 36 days [23–25]. Risperidone [23] and
aripiprazole [24] were included for assay sensitivity (i.e. as
positive controls), and comparison between these drugs and
cariprazine was not the focus of the studies; thus, these
patient groups are not discussed in detail.
The primary endpoint was change from baseline to week
6 in PANSS total score, using last-observation-carried-
K. P. Garnock-Jones
forward (LOCF) imputation [23] or a mixed-effects model
for repeated measures (MMRM) [24, 25], in the modified
intent-to-treat (mITT) population. In general, there were no
significant differences in patient demographics or baseline
characteristics [23–25]; one study reported a slight imbal-
ance in previous suicide attempts and a significant
(p = 0.045) difference in CGI-S scores across treatment
groups (Table 1) at baseline [23]. The mean duration of
schizophrenia was 10.7–12.2 years, the mean number of
previous psychiatric hospitalizations was 4.1–7.4, and
15.9–19.6% of patients had a history of suicide attempt
[23–25]. In the study that reported schizophrenia subtypes,
the majority of patients had paranoid schizophrenia (89%)
[23].
Cariprazine was associated with a significantly greater
change from baseline to 6 weeks in PANSS total score than
placebo, at all dosages (Table 1) [23–25]. The least squares
mean difference (LSMD) between cariprazine and placebo
recipients in PANSS total score ranged from -6.0 to
-10.4, across the dosages [23–25]. Sensitivity analyses
using an MMRM [23] or LOCF imputation [24, 25] con-
firmed these results.
A significant difference between cariprazine and pla-
cebo recipients in PANSS total score was first observed at
week 1 with cariprazine 3 [23], 4.5 [23], 6 [24] and
6–9 mg/day [25], at week 2 with cariprazine 1.5 [23] and
3–6 mg/day [25], and at week 3 with cariprazine 3 mg/day
[24], and continued throughout the 6 weeks [23–25].
At 6 weeks, the decrease in CGI-S scores was also
significantly greater in cariprazine than placebo recipients,
at all dosages, with LSMDs from placebo ranging from
-0.3 to -0.6 (Table 1) [23–25]. Moreover, cariprazine
was consistently associated with significantly lower Clini-
cal Global Impression-Improvement (CGI-I) scores than
placebo (Table 1) [23–25]. Treatment differences in
PANSS response rate were mixed; cariprazine 1.5, 3 and
4.5 mg/day in one study [23] and cariprazine 6 mg/day
[24] in another were associated with a significantly greater
response rate than placebo, but cariprazine 3 mg/day
recipients in one study [24] and cariprazine 3–6 and
6–9 mg/day recipients in another [25] did not significantly
differ from placebo recipients (Table 1).
Across all dosages, cariprazine was significantly more
efficacious than placebo at improving PANSS positive
subscale scores (Table 1) [23–25]. This was also generally
the case with regard to PANSS negative subscale scores
(Table 1), with significantly greater improvements
observed in cariprazine recipients than placebo for all
cariprazine dosages in two studies [23, 24] and for the
6–9 mg/day dosage in the third study [25]; recipients of
cariprazine 3–6 mg/day did not significantly differ from
placebo recipients in PANSS negative subscale score
improvements in this study [25].
Cariprazine: A Review 517

Table 1 Efficacy of oral cariprazine in patients with acute exacerbation of schizophrenia in the 6-week, phase IIb [23] and III [24, 25] studies

Study Treatment Change from BL in PANSS score [BL] Change from BL PANSS CGI-I
(mg/day) c
in CGI-S scorea responseb score
[no. of pts] Total Positive Negative [BL] rate (% pts)

Durgam CAR 1.5 [140] -19.4*** [97.1] -6.1** [25.2] -4.2*** [24.3] -1.0** [4.7] 31.4* 3.0**
et al. [23] CAR 3 [140] -20.7*** [97.2] -7.0*** [25.5] -4.5*** [24.5] -1.1*** [4.9] 35.7** 2.9***
CAR 4.5 [145] -22.3*** [96.7] -7.5*** [25.5] -5.0*** [24.5] -1.3*** [4.8] 35.9*** 2.8***
RIS 4d [138] -26.9*** [98.1] -9.5*** [25.4] -5.1*** [25.2] -1.5*** [4.8] 43.5*** 2.5***
PL [148] -11.8 [97.3] -4.1 [25.4] -2.0 [25.2] -0.7 [4.9] 18.9 3.5
Durgam CAR 3 [151] -20.2** [96.1] -6.8* [25.3] -4.4** [24.0] -1.4** [4.9] 24.5 2.7***
et al. [24] CAR 6 [154] -23.0*** [95.7] -7.5*** [24.6] -4.7*** [24.2] -1.5*** [4.8] 31.8* 2.7***
ARI 10d [150] -21.2*** [95.6] -7.2** [24.7] -4.2* [24.3] -1.4*** [4.8] 30.0* 2.7***
PL [149] -14.3 [96.5] -5.3 [24.6] -3.0 [25.0] -1.0 [4.8] 19.5 3.2
Kane et al. [25] CAR 3–6 [147] -22.8** [96.3] -7.8** [NR] -4.3 [NR] -1.4* [4.8] 28.6 2.6***
CAR 6–9e [147] -25.9*** [96.3] -9.1*** [NR] -5.0** [NR] -1.6*** [4.9] 34.7 2.4***
PL [145] -16.0 [96.6] -5.8 [NR] -3.4 [NR] -1.0 [4.9] 24.8 3.2
BL and CGI-I values are means; change-from-BL values are least squares means
ARI oral aripiprazole, BL baseline, CAR cariprazine, CGI-I Clinical Global Impression-Improvement scale, CGI-S Clinical Global Impression-
Severity scale, NR not reported, PANSS Positive and Negative Syndrome Scale, PL placebo, pts patients, RIS oral risperidone
* p \ 0.05, ** p B 0.01, *** p B 0.001 vs. PL
a
Secondary endpoint
b
Defined as a C30% improvement from BL in PANSS total score
c
Primary endpoint
d
RIS and ARI were included for assay sensitivity; comparison between these drugs and CAR was not the study focus
e
Dosages of [6 mg/day are not recommended by the US prescribing information (Sect. 6) [6]

Cariprazine was associated with a significantly
(p B 0.01) greater improvement than placebo in the
16-item Negative Symptom Assessment (NSA-16) total
score for all dosages in two studies [23, 24] and the car-
iprazine 6–9 mg/day dosage in the third study (but not
cariprazine 3–6 mg/day) [25], and in NSA-16 global neg-
ative symptom rating for all dosages in two studies [23, 24]
but neither dosage in the third [25].
With regard to other endpoints, one study [24] reported
that cariprazine 3 and 6 mg/day were also associated with
significantly (p \ 0.05) greater improvements in PANSS
general psychopathology, PANSS cognitive, PANSS
depression, and Cognitive Drug Research (CDR) continu-
ity of attention scores than placebo, and cariprazine
3 mg/day, but not 6 mg/day, was associated with a sig-
nificantly (p B 0.01) greater improvement in CDR power
of attention score than placebo. Another study reported no
significant differences between cariprazine 3–6 or
6–9 mg/day and placebo recipients in CDR attention bat-
tery [25]. No significant differences between cariprazine
and placebo recipients were found in CDR cognitive
reaction time and reaction time variability [24] or on the
Color Trails Test [24, 25].
Quality of life data were mixed, where reported [24, 25].
Schizophrenia Quality of Life Scale-Revision 4 (SQLS-R4)
total, vitality and psychosocial scores were all improved to
a significantly (p B 0.01) greater extent with cariprazine 3
and 6 mg/day than placebo in one study [24]. However,
another study found that while cariprazine 3–6 mg/day
recipients had significantly (p \ 0.05) greater improve-
ments than placebo recipients in SQLS-R4 total and vitality
scores, but not SQLS-R4 psychosocial scores, cariprazine
6–9 mg/day and placebo recipients did not significantly
differ in any of these measures [25].
Patients with schizophrenia have an increased risk of
hostile behaviour; cariprazine is associated with a sig-
nificantly greater improvement than placebo on the
PANSS hostility item, according to a post-hoc, pooled
analysis of the three 6-week trials (n = 1466) [27]. The
unadjusted LSMD in change from baseline to week 6
between cariprazine (all dosages pooled) and placebo
recipients was -0.28 (95% CI -0.41 to -0.15)
[p \ 0.0001]. This difference remained significant
(p \ 0.05) when adjusted for PANSS positive symptoms,
PANSS positive symptoms and sedation, and baseline
levels of hostility.
Indeed, cariprazine appears to have broad efficacy
across the range of schizophrenia symptoms. Another post-
hoc, pooled analysis of the three 6-week trials (n = 1466)
found that cariprazine was significantly more efficacious
518
than placebo in improving all PANSS Marder factors
(p \ 0.01), the PANSS cognitive factor (p \ 0.0001), and
26 of the 30 PANSS single items (p \ 0.05) [no significant
difference in somatic concerns, guilt feelings, motor
retardation or grandiosity scores] [28].
A post-hoc, pooled sub-group analysis of these three
trials found that significantly more cariprazine than placebo
recipients improved from more severe CGI-S categories at
baseline to less severe categories at week 6 [29]. In patients
who were severely ill at baseline (CGI-S scores C6;
n = 161), 42% of cariprazine versus 18% of placebo
recipients improved to mildly ill or better (CGI-S scores
B3) [p = 0.004]. In patients who were markedly ill or
worse at baseline (CGI-S scores C5; n = 1033), 7 versus
3% improved to borderline ill/normal (CGI-S scores B2)
[p = 0.022] [29].
4.1 In Patients with Predominant Negative
Symptoms
In a phase IIIb study, a total of 461 patients aged
18–65 years with predominant negative symptoms of
schizophrenia [defined as a PANSS-Factor Score for
Negative Symptoms (FSNS) C24 and a score of C4 on at
least two of the three core negative symptoms, for
C6 months] and low levels of positive symptoms were
randomized to receive 26 weeks’ treatment with car-
iprazine at a target dosage of 4.5 (range 3–6) mg/day
(n = 230) or risperidone at a target dosage of 4 (range
3–6) mg/day (n = 231) [5]. During the first 2 weeks of this
double-blind treatment period, patients underwent cross-
titration and discontinued any previous antipsychotic
treatment. The median duration of treatment was 182 days,
and the mean dosage was cariprazine 4.2 mg/day and
risperidone 3.8 mg/day. Further inclusion criteria were
schizophrenia onset C2 years before screening and
stable condition for C6 months [5]. Exclusion criteria
included a PANSS-Factor Score for Positive Symptoms
(FSPS)[19, a score of C4 on two or more PANSS positive
items, and clinically relevant depression or extrapyramidal
symptoms.
The primary endpoint was the change from baseline to
26 weeks (or early termination) in PANSS-FSNS, using an
MMRM in the mITT population [5]. Baseline character-
istics were similar between treatment groups; most patients
had had fewer than five acute exacerbations (59.6%), and
the mean time since diagnosis of schizophrenia was
&12.5 years.
At week 26, cariprazine was associated with a signifi-
cantly greater improvement from baseline than risperidone
in PANSS-FSNS (Table 2; effect size 0.31) [5]. The
treatment difference was consistently significant (p \ 0.01)
at all timepoints from week 14 through 26 [5].
K. P. Garnock-Jones
Similarly, cariprazine was associated with a signifi-
cantly greater improvement from baseline in the secondary
endpoint, Personal and Social Performance scale (PSP)
total score (Table 2; effect size 0.48); this difference was
significant (p \ 0.01) from week 10 through 26 [5]. Car-
iprazine recipients also demonstrated significantly
(p \ 0.01) greater improvement than risperidone recipients
in PSP self-care area score, PSP socially useful activities
area score and PSP personal and social relationships area
score, but not in PSP disturbing and aggressive area score.
A significantly greater proportion of cariprazine than
risperidone recipients responded to treatment (defined as an
improvement of C20% in PANSS-FSNS) [69 vs. 58% of
patients; odds ratio 2.08; p = 0.0022], with a number
needed to treat for one additional response of 9 [5]. Car-
iprazine recipients also demonstrated significantly greater
changes in CGI-S score and significantly better CGI-I
scores than risperidone recipients after 26 weeks (Table 2)
[5]. PANSS total (Table 2), PANSS positive subscale score
(Table 2) and PANSS general psychopathology scores did
not significantly differ between groups.
Upon further analysis of pseudospecific effects,
improvements in positive, depressive or extrapyramidal
symptom were ruled out as factors in the observed
improvements in negative symptoms, with no significant
difference between cariprazine and risperidone in change
from baseline in PANSS-FSPS, Calgary Depression Scale
for Schizophrenia score, or Simpson-Angus Scale (SAS)
items 1–8 [5]. Changes in these scale scores were small
during the study.
Similarly, cariprazine was more efficacious than placebo
at improving PANSS-FSNS in post-hoc subgroup analyses
of patients with high levels of negative symptoms in
6-week, phase IIb [23] and III [24] trials (both individually
[30, 31] and pooled [32]). For example, in the pooled
analysis of both trials, the LSMD from placebo (n = 67) in
change from baseline to week 6 in PANSS-FSNS was -2.5
(95% CI -4.2 to -0.8; p = 0.0038) for cariprazine
1.5–3 mg/day (n = 85) and -3.7 (95% CI -5.5 to -1.9
[p \ 0.0001) for cariprazine 4.5–6 mg/day (n = 64) [32].
In this analysis, the control risperidone group (n = 34)
showed significant improvement versus the placebo group
(LSMD -2.5; 95% CI -4.7 to -0.3; p = 0.0258), but the
control aripiprazole group (n = 35) did not (LSMD -1.0;
95% CI -3.1 to 1.2).
4.2 Prevention of Relapse
This long-term study included an 8-week, flexible-dose,
open-label, run-in phase, followed by a 12-week, fixed-
dose, open-label, stabilization phase and a 26- to 72-week,
fixed-dose, double-blind phase [26]. During the run-in
phase, patients were individually titrated to cariprazine 3, 6
Cariprazine: A Review
Table 2 Efficacy of 26 weeks’ treatment with cariprazine versus risperidone in patients with predominantly negative symptoms of
schizophrenia [5]
CAR 3–6 mg/day (n = 227)
LSM change from BL [BL]
PANSS-FSNSa -8.90 [27.7]
PSP total scoreb ?14.30 [48.8]
PANSS total score -16.90 [NR]
PANSS positive score -1.40 [8.7]
CGI-S score -0.95 [NR]
CGI-I score 2.53
The mixed-effects model for repeated measures used for the primary and secondary endpoints differed from that used for other endpoints
BL baseline, CAR cariprazine, CGI-I Clinical Global Impressions-Improvement scale, CGI-S Clinical Global Impressions-Severity scale,
LSM least-squares mean, LSMD LSM difference, NR not reported, PANSS Positive And Negative Syndrome Scale, FSNS Factor Score for
Negative Symptoms, PSP Personal and Social Performance scale, RIS risperidone
* p \0.01, ** p \ 0.0001
a
Primary endpoint
b
Secondary endpoint
or 9 mg/day, as required; they received fixed dosages
during the final two weeks of this phase, and continued on
the same fixed dosage through the stabilization phase. At
the end of the stabilization phase, patients were random-
ized to receive cariprazine at the same dosage as the pre-
vious phase (n = 101) or placebo (n = 99) during the
double-blind phase. Cariprazine dosages of [6 mg/day are
not recommended by the US prescribing information
(Sect. 6) [6].
Inpatients aged 18–60 years with a current DSM-IV-TR
diagnosis of schizophrenia (for C1 year) and a current
psychotic episode of \4 weeks’ duration were included in
the study [26]. Further inclusion criteria were a PANSS
total score of 70–120 and a score of C4 on at least two of
the PANSS positive symptoms delusions, hallucinatory
behaviour, conceptual disorganization and suspiciousness/
persecution. Exclusion criteria included a first psychotic
episode, or various other relevant disorders.
To progress from the run-in to the stabilization and
double-blind phases of the study, patients were required to
have a PANSS total score B60; a C20% decrease from
baseline in PANSS total score; a CGI-S score B4; a score
of B4 on each of the seven PANSS items delusion, con-
ceptual disorganization, hallucinatory behaviour, suspi-
ciousness/persecution, hostility, uncooperativeness and
poor impulse control; and no significant tolerability issues
[26]. All patients were hospitalized during the first 2 weeks
of the run-in phase, after which they were discharged or
hospitalized for a further 2 weeks. If they were unable to
be discharged after 4 weeks, they were discontinued from
the study.
The primary endpoint was time to first relapse (defined
by objective rating-scale criteria and subjective clinical
measures) during double-blind treatment, in the mITT
519
RIS 3–6 mg/day (n = 229) LSMD (95% CI)
-7.44 [27.5] -1.46 (-2.39 to -0.53)*
?9.66 [48.1] ?4.63 (2.71–6.56)**
-14.80 [NR] -2.10 (-4.34 to 0.13)
-1.41 [8.6] ?0.01 (-0.52 to 0.54)
-0.74 [NR] -0.21 (-0.36 to -0.06)*
2.89 -0.37 (-0.55 to -0.19)**
population [26]. While the two treatment groups generally
did not significantly differ at baseline with regard to patient
demographics, there were significantly more men in the
placebo than in the cariprazine group during the double-
blind phase (71 vs. 61%; p = 0.0361). At the beginning of
the open-label phase, 93% of patients had paranoid
schizophrenia, the mean duration of illness was 12.9 years,
the duration of the current episode was 2.2 weeks, patients
had had a mean of 6.4 prior hospitalizations, and 9 and
16% of patients had a history of violent behaviour and
suicide attempts, respectively. At the beginning of the
double-blind phase, the cariprazine dosage was 3 mg/day
in 14 patients, 6 mg/day in 37 patients, and 9 mg/day in
50 patients [26].
Cariprazine recipients had a significantly (p = 0.001)
longer time to relapse than placebo recipients (Fig. 1), with
a median time to relapse that had not yet been reached in
cariprazine recipients (vs. 296 days in placebo recipients),
and a hazard ratio for relapse of 0.45 (95% CI 0.28–0.73)
[26]. After 26 weeks, 24.8 and 47.5% of cariprazine and
placebo recipients had relapsed; the most common reasons
for relapse were an increase in PANSS total score of C30%
(in patients with scores C50 at randomization) or
C10 points (in patients with scores \50 at randomization)
[20.8 vs. 43.4%], a score [4 on one of the seven PANSS
items (10.9 vs. 25.3%), and an increase of C2 in CGI-S
score (4.0 vs. 28.3%).
The rates of relapse at week 2 (2% of cariprazine and
2% of placebo recipients), week 4 (7 and 3%) and week 6
(8 and 12%) were similar between groups; rates began to
diverge at week 8 (11 and 19%), although statistical
analyses were not reported for this timepoint [26].
Following improvements from baseline in PANSS total
score, PANSS positive subscale score, PANSS negative
520
60
Cumulative Incidence (%)
50
40 Time to relapse for cariprazine vs placebo: P=.001
30
20
10
Cariprazine 3-9 mg/d
Placebo
0
0 50 100 150 200 250 300 350 400 450 500 550
Duration of Double-Blind Treatment (days)
Fig. 1 Cumulative rate of relapse with cariprazine versus placebo in
patients with schizophrenia, during the 26- to 72-week double-blind
phase of the phase III relapse-prevention study [26]. Dosages of
[6 mg/day are not recommended by the US prescribing information
(Sect. 6) [6]. Reproduced from Durgam et al. [26], with permission
subscale score, CGI-S score, and NSA-16 total score dur-
ing the open-label phase, changes from randomization were
numerically greater among placebo than cariprazine
recipients in these endpoints during the double-blind,
relapse-prevention phase (statistical analyses were not
performed) (Table 3) [26]. Mean CGI-I score at the end of
treatment was 2.5 in cariprazine and 3.1 in placebo recip-
ients (at the end of the open-label phase, CGI-I score was
2.8).
5 Tolerability of Cariprazine
Cariprazine is generally well tolerated in patients with
schizophrenia, with most adverse events of mild to mod-
erate severity in clinical trials [6, 23–26, 33]. In the 6-week
trials, the overall incidence of treatment-emergent adverse
events ranged from 61 to 78% in cariprazine recipients
(across all dosages), versus 66–67% in placebo recipients
[23–25]. Where reported in the 6-week trials, significant
treatment differences in the incidence of specific adverse
events included akathisia (7 and 15 vs. 5% in cariprazine 3
and 6 mg/day vs. placebo recipients; p \ 0.05 for car-
iprazine 6 mg/day vs. placebo) and worsening of
schizophrenia (2 and 3 vs. 8%, respectively; both p \ 0.05)
[24].
Across all dosages, serious adverse events occurred in
0–6% of cariprazine and 1–15% of placebo recipients in
these studies [23–25]. Of the serious adverse events, the
only events reported in more than one patient were psy-
chotic behaviour (three placebo recipients) in one study
[23], and schizophrenia (two cariprazine 3 mg/day and one
cariprazine 6 mg/day recipients), social stay hospitalization
(one cariprazine 6 mg/day and one placebo recipient), and
psychotic disorder (two cariprazine 3 mg/day recipients) in
another [24]; the third 6-week study reported that most
K. P. Garnock-Jones
serious adverse events involved worsening of schizophre-
nia [25]. Where reported, serious adverse events that were
considered to be related to study treatment occurred in one
cariprazine 3 mg/day recipient (supraventricular tachycar-
dia; resolved within one week of discontinuation) in one
study [24], and one placebo recipient (exacerbation of
schizophrenia), three cariprazine 3–6 mg/day recipients
(one each of hyponatremia, psychotic relapse, psychotic
exacerbation; all three patients discontinued treatment),
and three cariprazine 6–9 mg/day recipients (one each of
hepatitis and worsening of psychosis, and one patient with
irregular pulse and increased blood pressure; all three
patients discontinued treatment) in another [25].
A total of 6–13% of cariprazine and 9–11% of placebo
recipients discontinued treatment as a result of adverse
events [23–25]. No treatment-related deaths occurred in
these studies [23–25]. The most common adverse events
observed in a pooled analysis [6] of four 6-week trials are
shown in Fig. 2.
The most common adverse event in the pooled analysis
of the 6-week trials was extrapyramidal symptoms; of
these, parkinsonism was the most common, with an inci-
dence of 13 and 16 versus 7% in cariprazine 1.5–3 and
4.5–6 mg/day versus placebo recipients. Akathisia was the
next-most common, at 9 and 13 versus 4%, respectively
[6]. In individual trials, no statistically significant differ-
ences between groups were observed in Barnes Akathisia
Rating Scale (BARS) and SAS scores [23–25].
In patients with predominantly negative symptoms of
schizophrenia, adverse events occurred in similar propor-
tions of cariprazine and risperidone recipients over the
26-week, double-blind treatment period (53 vs. 57% of
patients) [5]. Serious adverse events occurred in 3% of
patients in both groups [most commonly schizophrenia (2%
in each group)], and there were no treatment-related deaths
during the study. The most common (incidence [5% in
either group) adverse events were insomnia (9 vs. 10%),
akathisia (8 vs. 5%), schizophrenia (7 vs. 4%), headache (6
vs. 10%), anxiety (6 vs. 5%), somnolence (4 vs. 6%), and
dizziness (2 vs. 5%). Extrapyramidal symptoms (including
akathisia and restlessness) occurred in 14 and 13% of
patients (akathisia occurred in 8 and 5%). During the whole
study, including a 2-week safety follow-up period, most
adverse events were of mild to moderate severity, and 10
and 12% of cariprazine and risperidone recipients discon-
tinued as a result of adverse events (2 and 3% as a result of
serious adverse events).
As plasma levels of cariprazine and its metabolites
accumulate over time (Sect. 3), adverse events may occur
for the first time several weeks after treatment initiation;
thus, short-term trials may not accurately reflect the overall
tolerability profile of cariprazine [6]. Generally, tolerability
data from the relapse-prevention trial [26] and the 48-week
Cariprazine: A Review 521

Table 3 Changes in efficacy scores from randomization to end of treatment during the 26- to 72-week double-blind phase of the phase III
relapse-prevention study in patients with schizophrenia [26]. Baseline data are presented in square brackets

Treatment No. of pts PANSS CGI-S NSA-16 total PSP

(mg/day)
Total Positive Negative

CAR 3–9a 101 ?5.0 [51.3] ?1.3 [11.8] ?1.4 [14.2] ?0.1 [2.8] ?0.6 [39.1] 0.0 [66.8]
PL 99 ?13.2 [50.5] ?4.3 [11.5] ?2.4 [14.3] ?0.7 [2.6] ?4.1 [38.2] -7.2 [68.3]
CAR cariprazine, CGI-S Clinical Global Impressions-Severity scale, NSA-16 16-item Negative Symptom Assessment scale, PANSS Positive
And Negative Syndrome Scale, PL placebo, pts patients, PSP Personal and Social Performance scale
a
Dosages of [6 mg/day are not recommended by the US prescribing information (Sect. 6) [6]

Extrapyramidal symptoms
Insomnia
Akathisia
Somnolence
Constipation
Nausea
Restlessness
Anxiety Cariprazine 1.5-3 mg/d (n = 539)
Cariprazine 4.5-6 mg/d (n = 575)
Vomiting
Placebo (n = 584)
Dyspepsia
Agitation
Dizziness
0 5 10 15
Incidence (% of patients)
Fig. 2 Tolerability of cariprazine 1.5–6 mg/day in patients with
schizophrenia in a pooled analysis of four 6-week trials [6]. Incidence
of adverse events occurring in C5% of cariprazine 1.5–3 or
4.5–6 mg/day recipients at an incidence greater than that in placebo
recipients
extensions [34, 35] of the 6-week trials were similar to
those in the 6-week trials.
In the double-blind phase of the relapse-prevention trial,
the incidence of treatment-emergent adverse events was
74% in cariprazine and 65% in placebo recipients (44.6 and
32.3% of patients had treatment-related adverse events);
the incidence of serious adverse events was 14 and 14%,
the incidence of newly emergent adverse events was 70 and
65%, and 14 and 15% of patients discontinued treatment as
a result of adverse events [26]. Most adverse events were of
mild to moderate severity, and no patients died during this
study.
The most common treatment-emergent adverse events
(C5% of cariprazine recipients) during double-blind treat-
ment in the relapse-prevention trial were tremor (8% of
cariprazine vs. 0% of placebo recipients), nasopharyngitis
(8 vs. 5%), insomnia (8 vs. 8%), worsening of
schizophrenia (8 vs. 13%), headache (7 vs. 7%),
extrapyramidal disorders (6 vs. 3%), back pain (5 vs. 2%),
akathisia (5 vs. 3%) and increased blood creatine phos-
phokinase levels (5 vs. 3%) [26]. The only serious adverse
events occurring in C2% of patients were worsening of
schizophrenia (7 vs. 7%) and psychotic disorder (2 vs. 2%).
Worsening of schizophrenia could be considered a lack of
response, rather than a lack of tolerability.
In an integrated analysis [36] of two 48-week exten-
sion trials (one an extension of the phase IIb trial [34], the
other an extension of the two phase III trials which also
included new patients [35]), involving 679 patients with
schizophrenia who received at least one dose of car-
iprazine 1.5–9 mg/day, treatment-emergent adverse events
were reported in 81% of patients [most commonly aka-
thisia (16%), insomnia (13%), headache (13%) and
increased bodyweight (11%)] and serious adverse events
20
in 12% [most commonly worsening of schizophrenia
(4%) and psychotic disorder (2%)]. One patient commit-
ted suicide (not considered to be treatment related [34]);
no other deaths occurred. Treatment-emergent parkin-
sonism (SAS score [3) and treatment-emergent akathisia
(BARS score [2) occurred in 11 and 18% of patients,
respectively [36].
5.1 Adverse Events of Special Interest
Elderly recipients of antipsychotic drugs who have
dementia-related psychosis are at an increased risk of all-
cause death (1.6–1.7 times that in placebo recipients; rate
of death &4.5% in antipsychotic drug vs. &2.6% in
placebo recipients in 10-week trials) [6]. Most deaths in
these patients appeared to be cardiovascular or infectious
in nature. As cariprazine is an antipsychotic drug, it is
not approved for use in patients with dementia-related
psychosis, and the US prescribing information carries a
boxed warning regarding this [6]. Placebo-controlled
trials involving elderly patients with dementia-related
psychosis also showed that the antipsychotic drugs
risperidone, aripiprazole and olanzapine were associated
with higher incidences of stroke and transient ischaemic
attack [6].
Cariprazine, as an antipsychotic drug, is associated with
an increased risk of potentially irreversible tardive dyski-
nesia, particularly in elderly patients [6]. As the risk of
developing tardive dyskinesia (and the risk of it becoming
522
irreversible) increases with duration of treatment and
cumulative dose, cariprazine should be administered at the
lowest dosage and for the shortest duration of treatment
possible, in appropriate patients. However, the syndrome
can develop after short treatment periods and at low
dosages, or after treatment discontinuation.
Atypical antipsychotics, such as cariprazine, have been
associated with metabolic changes (hyperglycaemia, dia-
betes mellitus, dyslipidaemia, weight gain) [6]. In a pooled
analysis of the 6-week trials in patients with schizophrenia,
proportions of patients with a change in fasting glucose
from normal (\100 mg/dL) or borderline (C100 to
\126 mg/dL) levels to high levels (C126 mg/dL) were
similar between cariprazine and placebo recipients. Long-
term, 4% of open-label cariprazine recipients with normal
baseline HbA1c levels developed elevated levels (C6.5%).
Proportions of patients with changes in fasting total
cholesterol, LDL, HDL and triglyceride levels were similar
between cariprazine and placebo recipients in the pooled
analysis [6]; however, one study reported significantly
(p \0.05) different mean changes in total cholesterol and
LDL levels in cariprazine 6 mg/day than in placebo
recipients (-4.5 vs. ?3.5 mg/dL and -4.1 vs. ?4.0 mg/dL,
respectively) [24].
After 6 weeks, the mean change in bodyweight was
?0.8 and ?1 versus ?0.3 kg in recipients of cariprazine
1.5–3 and 4.5–6 mg/day versus placebo; the proportions of
patients with a bodyweight change C7% were 8 and 8
versus 5%, respectively [6]. Long-term, the mean change
from baseline to week 12, 24 and 48 in cariprazine recip-
ients was ?1.2, ?1.7 and ?2.5 kg, respectively.
In the integrated analysis of the 48-week extension trials
[36], mean changes in metabolic parameters, other clinical
laboratory values, blood pressure and ECG parameters
were generally small. The mean change in bodyweight was
?2.46 kg. There was a mean decrease in prolactin levels
[36]. Similar results for metabolic changes were observed
in a pooled analysis of the 6-week trials and the two
48-week extension trials, which concluded that cariprazine
is not associated with increased incidence of metabolic
syndrome [37].
Atypical antipsychotics are also associated with an
increased risk of orthostatic hypotension and syncope [6].
In placebo-controlled clinical trials, cariprazine recipients
did not experience orthostatic hypotension at a greater
incidence than placebo, and it was rare in both groups [6].
No patients in either group reported syncope. Cariprazine
has not been investigated in patients with a recent history
of myocardial infarction or unstable cardiovascular disease.
There may be an association between the use of atypical
antipsychotics and the development of cataracts. Cataracts
K. P. Garnock-Jones
developed in 0.1% of patients after 48 weeks of treatment
with cariprazine; the possibility of an association with
cariprazine treatment cannot be excluded at this time [6].
Other warnings and precautions covered in the US
prescribing information include an increased risk of neu-
roleptic malignant syndrome; seizures; dysphagia; dysto-
nia; impaired judgement, thinking and motor skills; falls;
and leukopenia, neutropenia and agranulocytosis with
antipsychotic agents, and of body-temperature dysregula-
tion with atypical antipsychotics [6]. Caution and moni-
toring are advised; refer to the US prescribing information
for more details [6].
No clinically meaningful differences in change from
baseline in supine blood pressure parameters between
cariprazine at the recommended dosages of 1.5–6 mg/day
and placebo recipients were found in a pooled analysis of
the 6-week trials in patients with schizophrenia [6].
Increases in transaminase levels of C3 times the upper
limit of normal were observed in 1–2% of cariprazine
recipients (increasing incidence with increasing dosage)
and 1% of placebo recipients [6]. Increases in creatine
phosphokinase levels to [1000 U/L occurred in 4–6% of
cariprazine (increasing with dosage) and 4% of placebo
recipients [6].
While no data are available regarding cariprazine-asso-
ciated risks to the foetus in pregnant women, antipsychotic
drug use in the third trimester has been associated with an
increased risk of extrapyramidal and/or withdrawal symp-
toms in the neonate following delivery [6]. Pregnant
women should be advised of the potential risk [6]. The
presence of cariprazine in breastmilk and the effect on the
breastfeeding infant have not been investigated; cariprazine
is present in rat milk [6].
6 Dosage and Administration of Cariprazine
Oral, once-daily cariprazine is indicated in the USA for
the treatment of schizophrenia [6]. The recommended
starting dosage is 1.5 mg/day, and the dosage can range
from 1.5 to 6 mg/day, depending on clinical response and
tolerability. Cariprazine can be taken with or without
food.
As cariprazine and its active metabolites have long half-
lives, changes in dosage will not be fully evident in plasma
concentration for several weeks; patients should be moni-
tored for several weeks after each dosage change [6].
Cariprazine dosage adjustments may be required with
coadministration of strong CYP3A4 inhibitors; coadmin-
istration with CYP3A4 inducers is not recommended
(Sect. 3).
Cariprazine: A Review
The US prescribing information carries a boxed warning
regarding increased mortality in elderly patients with
dementia-related psychosis receiving antipsychotic drugs;
the use of cariprazine is not approved in patients with
dementia-related psychosis [6]. Local prescribing infor-
mation should be consulted for detailed information,
including contraindications, precautions, drug interactions
and use in special patient populations.
7 Place of Cariprazine in the Management
of Schizophrenia
Schizophrenia is a heterogeneous disorder that manifests
with a different mixture of positive and negative symptoms
in different patients [1]. Positive symptoms are generally
present only during acute episodes, whereas negative
symptoms can sometimes persist beyond these episodes,
and are more difficult to treat effectively [1, 3]; often, other
(adjunctive) drugs are used to treat negative symptoms,
such as antidepressants [5, 38]. Aside from effectiveness in
various symptoms of schizophrenia, other patient factors
may play a part in choosing treatment options (e.g. history
of poor health or comorbid conditions, patient preference,
route of administration, potential interactions with other
drugs, and cultural and ethnic differences in treatment
expectations and adherence) [1, 3]. The choice of
antipsychotic (either first- or second-generation) treatment
is often patient dependent, as, aside from the efficacy of the
drugs in the particular symptoms evident in each patient,
they may differ in adverse event profiles, including meta-
bolic factors (weight gain, diabetes), extrapyramidal events
(akathisia, dyskinesia), cardiovascular events (prolonged
QT interval), and hormonal effects (increased plasma
prolactin) [1, 3].
Most treatment guidelines for schizophrenia were pub-
lished well before the approval of cariprazine, and gener-
ally recommend individualized treatment with
antipsychotics, along with psychological interventions and
monitoring for common adverse events [1, 3, 39]. The
antipsychotic drugs commonly discussed include the first-
generation drugs haloperidol and chlorpromazine and the
second-generation drugs risperidone, aripiprazole, olanza-
pine and quetiapine [3, 39], although the use of first-gen-
eration drugs has declined considerably with the
availability of second-generation drugs [3].
The use of cariprazine in patients with schizophrenia
efficaciously reduced symptoms in 6-week clinical trials
(Sect. 4), including improvements in PANSS total, positive
and negative scores, as well as in CGI-S and CGI-I scores,
versus placebo. Post-hoc analyses found that cariprazine
523
may also have positive effects on cognitive factors and
reduce hostile behaviour.
Cariprazine has a higher affinity for the D3 than the D2
receptor (Sect. 2). The ultimate effects of blockading the
D3 receptor are unknown, although preclinical studies
imply that D3 receptor blockade may be associated with
pro-cognitive and antidepressant effects, and may improve
negative symptoms and stimulant abuse [7].
Interestingly, cariprazine is associated with improve-
ments in primary negative symptoms of schizophrenia;
moreover, these improvements are unlikely to result from
improved positive or overall symptoms. Cariprazine was
significantly more efficacious than risperidone in improv-
ing PANSS-FSNS over 26 weeks in patients with pre-
dominantly negative symptoms; the two treatments had
similar improvements in PANSS total and positive subscale
scores (Sect. 4.1). Significant improvements over risperi-
done were also observed in PSP total, CGI-S, and CGI-I
scores, as well as in PANSS-FSNS response rate and three
of four PSP subdomain scores.
The trial in patients with predominantly negative
symptoms of schizophrenia was conducted according to the
EMA-recommended guidelines for studies of negative
symptoms, and is the first large-scale study in these patients
that has shown a clinically significant improvement in
negative symptoms with an antipsychotic drug as
monotherapy (cariprazine) over another (risperidone)
[4, 5]. As the clinically significant effect sizes for PANSS-
FSNS and PSP total score were for cariprazine versus
another active drug, they may be even greater against
placebo; however, further independent analyses are nec-
essary to confirm this. Of further interest, the effect on
negative symptoms appeared to start later than in studies in
patients with acute, positive symptoms, implying a poten-
tially different mechanism of action for these effects [4].
Again, further independent research would be of interest in
this area. The results from this study may not be applicable
to efficacy with regard to secondary negative symptoms.
Without maintenance antipsychotic therapy, there is a
60–70% risk of relapse within 1 year (up to an almost 90%
risk within 2 years); antipsychotic treatment can reduce
this risk, in the stable phase, to\30% per year [3]. In a 26-
to 72-week study, cariprazine significantly increased the
time to first schizophrenia symptom relapse versus that
with placebo (Sect. 4.2).
Overall, cariprazine was generally well tolerated in
patients with schizophrenia; most adverse events in the
6-week trials were of mild to moderate severity (Sect. 5).
The most common adverse event was extrapyramidal
symptoms, and similar proportions of cariprazine to pla-
cebo recipients discontinued as a result of adverse events.
524
Cariprazine and risperidone had similar adverse event
profiles in patients with predominantly negative symptoms,
and tolerability data over longer periods of time were
generally similar to those observed in the 6-week trials.
Cariprazine is not approved in elderly patients with
dementia-related psychosis, as there is a higher risk of all-
cause death in these patients with antipsychotic drugs
(Sect. 5.1). Similar to other antipsychotics, cariprazine
carries a risk of tardive dyskinesia. Metabolic changes were
generally small in the long term, and were deemed not
clinically meaningful (Sect. 5.1).
Of the phase III trials discussed in this review, only the
negative-symptoms trial was designed to compared car-
iprazine with another antipsychotic, although two others
included other antipsychotics as positive controls. Beyond
this one study, there are insufficient data available to make
assumptions on which drug, if any, is more efficacious.
Well designed, head-to-head, independent trials comparing
cariprazine with popular second-generation antipsychotics
would be of great use in the placement of this drug for the
management of schizophrenia.
Cariprazine and its major active metabolites have very
long half-lives (Sect. 3). This may be an advantage, as
patients with schizophrenia often demonstrate poor com-
pliance with treatment [40]. A missed dose of cariprazine
may, theoretically, be associated with a lower risk of
relapse than that with a drug with a shorter half-life.
However, the longer half-life may also mean that it could
prolong the duration of adverse events that may occur,
beyond discontinuation of treatment. Further investigation
into the effects of these longer half-lives would be of
interest.
The phase IIb and III trials discussed in Sect. 4 did not
report detailed results concerning treatment compliance
within the trials. As noncompliance and partial compliance
are common issues with antipsychotic use in patients with
schizophrenia, investigation into how adherent patients are
to cariprazine treatment, and the effects of this on efficacy
and tolerability (and the reverse) would be of use, partic-
ularly in comparison with other antipsychotics. Nonad-
herence to treatment has been associated with poor
outcomes, such as relapse, rehospitalisation, longer time to
remission, attempted suicide, and substance use [40, 41],
and whether or not a patient is treatment compliant is often
associated with medication factors such as tolerability and
efficacy (as well as illness, caregiver, physician and patient
factors) [40].
In conclusion, cariprazine is an efficacious and generally
well tolerated treatment for schizophrenia. It is a useful
addition to the treatment options for this disorder, and may
be of particular use in patients with predominantly negative
symptoms.
K. P. Garnock-Jones
Data Selection Cariprazine: 123 records identified
Duplicates removed 23
Excluded at initial screening (e.g. press releases; news 21
reports; not relevant drug/indication)
Excluded during initial selection (e.g. preclinical study; 10
review; case report; not randomized trial)
Excluded by author (e.g. not randomized trials; review; 28
duplicate data; small patient number; phase I/II trials)
Cited efficacy/tolerability articles 18
Cited articles not efficacy/tolerability 23
Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to
present. Clinical trial registries/databases and websites were also
searched for relevant data. Key words were cariprazine, Vraylar,
RGH-188, MP-214, schizophrenia, schizophrenic. Records were
limited to those in English language. Searches last updated 28
April 2017
Acknowledgements During the peer review process, the manufac-
turer of cariprazine was also offered an opportunity to review this
article. Any changes resulting from comments received were made on
the basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any
external funding.
Conflict of interest Karly Garnock-Jones is a salaried employee of
Adis/Springer, is responsible for the article content and declares no
relevant conflicts of interest.
Additional information about this Adis Drug Review can be found at
http://www.medengine.com/Redeem/AB48F06045A02576.
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