Expert Opinion on Drug Discovery

ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: http://www.tandfonline.com/loi/iedc20

The preclinical discovery and development of

cariprazine for the treatment of schizophrenia

Anna Wesołowska, Anna Partyka, Magdalena Jastrzębska-Więsek & Marcin

Kołaczkowski

To cite this article: Anna Wesołowska, Anna Partyka, Magdalena Jastrzębska-Więsek & Marcin
Kołaczkowski (2018): The preclinical discovery and development of cariprazine for the treatment of
schizophrenia, Expert Opinion on Drug Discovery, DOI: 10.1080/17460441.2018.1471057

To link to this article: https://doi.org/10.1080/17460441.2018.1471057

Published online: 03 May 2018.

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EXPERT OPINION ON DRUG DISCOVERY, 2018
https://doi.org/10.1080/17460441.2018.1471057

DRUG DISCOVERY CASE HISTORY

The preclinical discovery and development of cariprazine for the treatment of

schizophrenia
Anna Wesołowskaa, Anna Partykaa, Magdalena Jastrzębska-Więseka and Marcin Kołaczkowskib
a
Department of Clinical Pharmacy, Jagiellonian University Medical College, Kraków, Poland; bDepartment of Pharmaceutical Chemistry, Jagiellonian
University Medical College, Kraków, Poland

ABSTRACT ARTICLE HISTORY

Introduction: Cariprazine is approved in the United States and Europe for the treatment of manic or Received 1 February 2018
mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult Accepted 26 April 2018
patients. It is typically administered orally once a day (a dose range 1.5 – 6 mg/day), does require KEYWORDS
titration, and may be given with or without food. It has a half-life of 2 – 4 days with an active metabolite Abuse; bipolar mania;
that has a terminal half-life of 2 – 3 weeks. cariprazine; cognition;
Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details depression; rodent models;
regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to schizophrenia
clinical therapeutic benefits. This article is based on the available literature with respect to the
preclinical and clinical findings and product labels of cariprazine.
Expert opinion: Cariprazine shows highest affinity toward D3 receptors, followed by D2, 5-HT2B, and 5-
HT1A receptors. It also shows moderate affinity toward σ1, 5-HT2A, and histamine H1 receptors. Long-
term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate
receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward
its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia,
bipolar mania, and possibly other psychiatric disorders.

1. Introduction Cariprazine is well absorbed after oral administration and

reaches the maximum peak plasma levels within approxi-
Cariprazine (US brand name: Vraylar®) was approved by the US
mately 3–8 h following multiple-dose administration. A high-
Food and Drug Administration (FDA) on 17 September 2015 for
fat meal (900–1000 calories) did not significantly affect Cmax or
the treatment of acute manic or mixed episodes associated with
the area under the curve (AUC) of cariprazine, which indicates
bipolar I disorder and for the treatment of schizophrenia in adults
that the effect of food on the exposure of cariprazine’s two
[1]. Cariprazine capsules are currently available in four strengths,
primary metabolites (desmethylcariprazine (DCAR) and dides-
in the following color: 1.5 mg (white cap and body imprinted
methylcariprazine (DDCAR)) was also minimal. Absolute bioa-
with ‘FL 1.5’), 3 mg (green to blue-green cap and white body
vailability of cariprazine is still unknown. The parent
imprinted with ‘FL 3’), 4.5 mg (green to blue-green cap and body
compound and its major active metabolites are highly
imprinted with ‘FL 4.5’), and 6 mg (purple cap and white body
bound (96–97% for cariprazine, 94%–97% for DCAR, and
imprinted with ‘FL 6’). In Europe, cariprazine (EU brand name:
92%–97% for DDCAR) to plasma proteins [1,2], an important
Reagila®) has been used for the treatment of schizophrenia in
fact to be considered during the treatment of comorbidities.
adult patients since 6 June 2017, in the form of hard capsules
The half-life of terminal disposition of cariprazine was found to
containing 1.5, 3, 4.5, and 6 mg of the active substance for oral
be 5–6 days and the elimination of its active metabolite
use, to be taken once daily at the same time of the day with or
DDCAR was found to be prolonged with an apparent terminal
without food [2]. The recommended starting dose of cariprazine
half-life of 2–3 weeks in healthy male volunteers [3]. A similar
is 1.5 mg. Thereafter, the dose can be increased slowly in 1.5 mg
pharmacokinetic profile has been observed for cariprazine in
increments to a maximum dose of 6 mg/day, if needed. Because
male patients with schizophrenia [4,5].
of the long half-life of cariprazine and its active metabolites,
Cariprazine is metabolized by CYP3A4 and, to a lesser extent,
changes in a dose will not be fully reflected in plasma for several
by CYP2D6 enzymes [6,7]. The parent compound and its major
weeks. Switching from other antipsychotics to cariprazine should
active metabolites are not substrates of P-glycoprotein, the
be made with caution and gradual cross-titration should be
organic anion transporting polypeptides 1B1 and 1B3, and the
considered, with gradual discontinuation of the previous anti-
breast cancer resistance protein. This suggests that cariprazine
psychotic while cariprazine treatment is initiated. Concomitant
does not interact with inhibitors of the aforementioned proteins.
smoking following oral administration had no effect on the
However, at its theoretical maximum intestinal concentration,
dosage of cariprazine.

CONTACT Anna Wesołowska a.wesolowska@uj.edu.pl Jagiellonian University Medical College, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688
Kraków, Poland
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. WESOŁOWSKA ET AL.
Article highlights
● Cariprazine is approved in the United States and Europe for the
treatment of manic or mixed episodes associated with bipolar I
disorder and the treatment of adult patients with schizophrenia. It
is typically administered orally once a day, does require titration, may
be given with or without food, has active metabolites with a half-life
of 2-3 weeks and highly bound to plasma proteins.
● Clinical trials reported that cariprazine is generally safe when admi-
nistered at a recommended dose range of 1.5 - 6 mg/day for
schizophrenia.
● Cariprazine shows highest affinity toward D3 receptors, followed by
D2, 5-HT2B, and 5-HT1A receptors. It also shows moderate affinity
toward σ1, 5-HT2A, and histamine H1 receptors, and negligible affinity
toward a wide range of neurotransmitter receptors, transporters, and
enzymes. It is D3/D2 receptor partial agonist.
● Behavioral studies indicated that cariprazine is active in different
animal models predictive of antipsychotic, antidepressant and anxio-
lytic activity. It also displays procognitive effects in several animal
models of memory, cognitive and executive functions in rodents.
● Following are the advantages of cariprazine treatment: clinical ability
in improving negative symptoms, ability to be useful in young
patients with a relatively short duration of schizophrenia, ability to
decrease substance abuse, and/or ability to maintain efficacy in cases
of missed doses.
● Further trials are warranted to evaluate the long-term efficacy of
cariprazine and its metabolic profile. Preclinical discovery and clinical
development of cariprazine should expand the therapeutic options
available for improved treatment of schizophrenia and bipolar mania,
and other psychiatric/cognitive disorders.
cariprazine has shown effectiveness as an in vitro P-glycoprotein
inhibitor. Although the clinical consequences of this effect is not
fully understood, the use of P-glycoprotein substrates with a
narrow therapeutic index such as dabigatran (an anticoagulant)
and digoxin (used for treating heart failure) might require extra
monitoring and dose adjustment [2]. Cariprazine may show sig-
nificant interaction with strong to moderate CYP3A4 inhibitors or
inducers. CYP2D6 inhibitors are unlikely to have a clinically rele-
vant effect on the pharmacokinetic properties of cariprazine. It is
not necessary to adjust the dose of cariprazine in patients with
mild to moderate hepatic or renal impairment. However, it is not
recommended for patients with severe hepatic or renal impair-
ment [2]. Cariprazine is generally well tolerated. The pooled
analysis of four short-term clinical trials showed that cariprazine
at doses of 1.5–12 mg/day was generally safe. Patients receiving
a dose over 6 mg/day showed a greater likelihood for adverse
events, akathisia and Parkinsonism, increase in weight, and
changes in blood pressure, as well as increased rates of creatine
phosphokinase and transaminases [8]. Hence, the recommended
dose range for schizophrenia is 1.5–6 mg/day. Moreover, caripra-
zine in randomized Phase II [9] and Phase III [10] 6-week clinical
trials showed no clinically relevant effects on sedation, QT pro-
longation, or prolactin elevation, issues commonly encountered
with antipsychotic treatment.
2. Pharmacology of cariprazine
Cariprazine (trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]
ethyl]cyclohexyl]-N’,N’-dimethyl-urea hydrochloride) was
selected from a series of new piperazine/piperidine derivatives
demonstrating high affinity to both dopamine D3 and D2
receptors as the most promising compounds [11] because it
can cross the blood–brain barrier, has a better safety profile,
and has unique receptor actions. Binding affinities of cariprazine
were determined using cloned human receptors or membrane
fractions prepared from rat tissues. It displayed picomolar affinity
toward human dopamine D3 (pKi = 10.07) and subnanomolar
affinity toward rat D3 (pKi = 9.15) receptors, both D2L (pKi = 9.31)
and D2S (pKi = 9.16) subtypes of human D2 as well as human 5-
HT2B (pKi = 9.24) receptors, and slightly lower for human
(pKi = 8.59) and rat (pKi = 8.34) 5-HT1A ones [12]. However,
another study demonstrated a similar affinity of cariprazine
toward the cloned human 5-HT1A and D2 receptors (both pKi
around 9.0) [13]. As it is shown above, the preference of caripra-
zine for rat and human D3 versus D2 receptors is similar. This
difference is not observed for binding to human and rat 5-HT1A
receptors. Moreover, the affinity of cariprazine toward the human
D3 receptors was not found to be affected by the Ser9Gly poly-
morphism [14], which has been associated with tolerability and
response to antipsychotic treatment [15].
Cariprazine binds with moderate affinity to human σ1
(pKi = 7.74), 5-HT2A (pKi = 7.73), and histamine H1
(pKi = 7.63) receptors and shows low affinity (pKi<7.0) for 5-
HT7, 5-HT2C, α1A, and α1C receptors [12]. According to Kiss et al.
[12], cariprazine displays very low affinity (pKi<6.0) toward 5-
HT6, α1B-, α2A-, β-adrenoceptors, and dopamine and serotonin
transporters and negligible affinity toward a variety of neuro-
transmitter receptors, ion channels, and transporters, includ-
ing dopamines D1, D4.2, and D5; adenosine; cannabinoid;
cholecystokinin; corticotropin; estrogen; GABAA and GABAB;
glutamate AMPA, kainate, and NMDA subtypes; histamines
H2, H3, and H4; muscarinic M1-5; nicotinic; opiate δ, κ, and μ;
potassium channel HERG; serotonin 5-HT3, 5-HT4, and 5-HT5A
subtypes; sigma σ2; Ca2+ L-type and N-type channels; Na+ site-
1 and site-2 channels; and norepinephrine, adenosine, and
choline transporters, and enzymes.
In vitro functional receptor activity using different assays
has been studied on both G-protein-dependent and
G-protein-independent signaling pathways. The results
demonstrated that cariprazine either stimulates or inhibits
the activity of D3 and D2 receptors. According to Kiss et al.
[12], in the GTPγS-binding assay, cariprazine demonstrated
silent antagonistic activity against both CHO-hD3 and native
rat striatal D2 receptors with the highest antagonist potency
detected (pKb = 9.50 and pKb = 8.5, respectively) among the
various antipsychotic drugs tested, having no agonist activity.
In CHO cells expressing human D3 receptors, cariprazine
showed partial agonistic activity, as it inhibited forskolin-
induced cAMP accumulation presenting 10-fold higher
potency than aripiprazole [12]. In mouse A9 cells expressing
human D2L receptors and cotransfected with Gqo5 protein,
cariprazine was found to be a partial agonist, stimulating IP
formation (Emax ~ 30%) and preventing IP formulation
(pKb = 9.22) evoked by quinpirole, the selective D2 receptor
agonist [12]. Taking into account the results of in vitro func-
tional studies, it must be confirmed that, depending on the
signaling pathway linked to D3/D2 receptors, the profile of
cariprazine corresponds to a biased agonist activity which
was already proposed by De Deurwaerdere [16].

Cariprazine acts as a neutral antagonist of the rat 5-HT2B
receptor as it potently inhibited serotonin-induced contrac-
tion of isolated rat stomach fundus strips (IC50 = 12.9 nM)
having no effect by itself [12]. Moreover, the compound
potently stimulated [35S]GTPγS binding in membranes pre-
pared from rat hippocampus containing 5-HT1A receptors
and showed moderate intrinsic activity (Emax = 38.6%) as
compared to 8-OH-DPAT, a full agonist of these receptors.
In in vitro assays, cariprazine also showed moderate antag-
onistic activity toward 5-HT2A (inhibition of IP formation
(IC50 = 403 nM) in CHO cells evoked by the 5-HT2A receptor
agonist DOI) and histamine H1 (inhibition of the histamine-
induced contraction (IC50 = 149 nM) of isolated guinea pig
trachea) receptors [12].
A positron emission tomography (PET) study in monkeys
showed that administration of cariprazine at increasing doses
(30–300 µg/kg) resulted in a dose-dependent and saturable
striatal D2/D3 receptor occupancy approximately 94% after the
highest dose, whereas in the raphe nuclei, the occupancy of the
5-HT1A receptor was about 30%. These data confirmed in vitro
affinity cited above [17]. In a previous PET analysis, by utilizing a
D3 receptor-preferring radioligand such as 4-propyl-9-hydroxy-
naphthoxazine ([3H]-(+)-PHNO), the authors demonstrated that
cariprazine at a dose of 1 mg/kg completely inhibited the uptake
of this radioligand in rat cerebellum [18]. In healthy subjects,
cariprazine occupied 3–79% of striatal D2/D3 receptors when
measured 4 h after 0.5–1 mg doses repeated for 2–12 days [19].
Using PET with [11C]-(+)-PHNO scans performed in patients with
schizophrenia, Girgis et al. [20] demonstrated a dose–occupancy
relationship for D3 and D2 receptors after 2 weeks of cariprazine
treatment. At a high dose of 12 mg/kg of cariprazine, nearly
100% occupancies were observed for both receptors.
Selectivity for D3 over D2 receptors were noted after lower
doses. An exposure-response analysis presented an ~ 3-fold
difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma
after 2 weeks of dosing [20]. All these results show the unique
receptor signature and functional activity of cariprazine and
support its distinct psychopharmacological profile for the
improved treatment of schizophrenia.
3. Neurochemical effects of cariprazine
Atypical antipsychotics are able to preferentially increase extra-
cellular concentrations of monoamines and acetylcholine in cor-
tical and limbic brain regions [21–24]. In vivo studies with
cariprazine focused primarily on dopaminergic and serotonergic
neuronal activity [12]. Cariprazine enhanced the turnover and
biosynthesis of dopamine in mouse brain, preferentially in olfac-
tory tubercles (i.e. limbic region) compared to the striatum.
Moreover, this compound potently and dose-dependently, but
only partially, reduced the dopamine biosynthesis in the striatum
of reserpinized mice and normalized a metabolite of dopamine
(3,4-dihydroxyphenylacetic acid) accumulation to the control
levels, reaching a plateau at the highest dose used. Cariprazine
showed lower potential in inhibiting dopamine neurotransmis-
sion in the striatum relative to the limbic area, which suggests
that it has low propensity toward causing extrapyramidal symp-
toms [12]. In addition, cariprazine moderately but significantly
EXPERT OPINION ON DRUG DISCOVERY 3
reduced serotonin turnover in all three regions studied: olfactory
tubercles, striatum, and frontal cortex [12].
4. Chronic effects of cariprazine
Extrapyramidal, limbic, and cortical regions of the brain
that mediate motor, emotional, and cognitive behaviors,
respectively, are typically disturbed in patients with schizo-
phrenia [25]. Furthermore, clinically effective antipsychotic
drugs produce region-specific changes in monoaminergic
and glutamatergic receptor subtypes’ levels. Chronic effects
of cariprazine on different neurotransmitter receptors were
evaluated in male Sprague Dawley rats receiving daily
intraperitoneal injections of three doses of cariprazine
active in behavioral paradigms, that is, 0.06, 0.20, or
0.60 mg/kg [26], for 28 days [27,28]. At the end of the
treatment, brains were collected and then processed for
quantitative in vitro receptor autoradiography using radi-
oligands that selectively label receptors of interest. Sections
were obtained from different brain regions that represent
extrapyramidal, limbic, and cortical systems. Cariprazine-
evoked changes in different receptors after repeated treat-
ment can be regarded as a functional index of its actions
because specific chronic drug–receptor interactions conse-
quently trigger changes in signal transduction cascades
and downstream neuronal elements and pathways, and
contribute to the clinical efficacy, safety, and tolerability
of the studied drug.
4.1. Dopamine receptors
Repeated doses of cariprazine induced a significant increase in
D3 receptors localized in forebrain regions [27], where they are
highly expressed. This effect appears to be unique for caripra-
zine since other (both typical and atypical) antipsychotics
(including haloperidol, fluphenazine, clozapine, olanzapine,
risperidone, and asenapine) did not evoke such changes in
all regions examined [29–32]. Moreover, cariprazine differen-
tially altered D3 receptor levels in the subdivisions of the
nucleus accumbens (NAc), shell and core, which are associated
with limbic and motor systems, respectively [33]. Cariprazine
significantly induced greater increases in D3 receptors loca-
lized in the NAc-shell versus NAc-core [27]. This finding further
supports the atypical antipsychotic profile of the drug because
it was reported that atypical antipsychotics (e.g. clozapine)
preferentially induce changes in dopamine levels in the NAc-
shell, whereas typical drugs (e.g. haloperidol) preferentially act
in the NAc-core [34]. Potent affinity of cariprazine for D3
receptors, its considerable D3 receptor occupancy
[12,17,18,20], partial agonist activity at these sites, and their
upregulation by the drug support its unique action among
antipsychotics that may be responsible for the normalization
of disturbances in D3 receptor-mediated neurotransmission in
patients with schizophrenia. In addition, unique actions of
cariprazine at these receptors may provide therapeutic bene-
fits in the treatment of negative symptoms of the disease,
cognitive, and executive deficits, and thanks to a concomitant
preference to the NAc-shell over the NAc-core – in the treat-
ment of mood symptoms as well as lesser extrapyramidal side
4 A. WESOŁOWSKA ET AL.

effects. In addition, in comparison to aripiprazole, cariprazine 4.3. Glutamate receptors

produced more profound increases in D3 receptors in many
Continuous administration (28 days) of cariprazine significantly
regions studied, especially in the NAc-shell [28] which is pro-
decreased the binding of an appropriate radioligand to NMDA
posed to be a common neurobiological mechanism of anti-
receptors in NAc and the medial and lateral caudate putamen
depressant treatment.
[28] evoking a similar effect to those reported for atypical (includ-
Long-term administration of cariprazine showed dose-
ing aripiprazole [28]), but not typical haloperidol [43–45] anti-
dependent upregulation of D2 receptors in the medial pre-
psychotics. Reduction in striatal NMDA receptors may result from
frontal cortex, NAc, and caudate putamen [27], which is char-
indirect interaction with dopamine and serotonin systems that
acteristic of both typical and atypical antipsychotics [28–
modulate glutamatergic transmission [46,47] in basal ganglia
30,32]. Cariprazine differs from typical neuroleptics in upregu-
which, at least in part, could be responsible for the benign
lating D2 receptors in the hippocampal areas as well, which
extrapyramidal effects of cariprazine. Repeated doses of caripra-
may explain some differences between the two classes of
zine also downregulated NMDA receptors in the hippocampal
antipsychotics. An increase in striatal D2 binding sites may
CA1 and CA3 subregions, the effect that may normalize the
account for higher clinical incidence of akathisia (9% versus
abnormalities in glutamatergic transmission occurring in the
15%) and extrapyramidal side effects (12% versus 5%) in car-
hippocampus of patients with schizophrenia, and subsequently
iprazine-treated patients than that of placebo-treated patients
improve their psychotic symptoms [48].
[35,36]. Long-term treatment with cariprazine also increased
Long-term treatment with cariprazine at doses of 0.2 and
the striatolimbic D4 receptor subtype [27], which appears to
0.6 mg/kg increased AMPA receptors in the hippocampal CA1
be a common mechanism of action for typical and atypical
and CA3 areas only [28] similar to aripiprazole [28] and asena-
antipsychotics [29–32].
pine [44]. Upregulation of ionotropic AMPA receptors may
Repeated treatment with different doses of cariprazine did
further contribute to the improvement of psychotic symptoms
not induce any changes in binding to D1 receptors in all the
of schizophrenia by direct action of cariprazine on D2 recep-
examined regions [27], which is a common feature of typical and
tors colocalized with AMPA in the brain [49]. Moreover, oppo-
atypical antipsychotics [30–32], except asenapine [29]. Because
site effects on NMDA versus AMPA receptors of cariprazine
of negligible affinity of cariprazine for D1 receptors, it is possible
suggest different ways of action of this D3/D2 partial agonist
that the drug did not occupy these sites to the extent required
on ionotropic glutamatergic binding sites.
to induce their upregulation as is the case with D4 receptors.
Moreover, similarly to atypical antipsychotics [37,38],
chronic (21 days) treatment with cariprazine suppressed pre-
5. Activity of cariprazine in behavioral models of
ferentially spontaneous activity of mesolimbic dopamine neu-
positive symptoms of schizophrenia
rons (45–66% at doses of 0.1–1.0 m/kg), but had no effects on
their activity in mesostriatal areas [39]. These data further 5.1. Apomorphine-induced climbing
support the utility of cariprazine as an antipsychotic drug
This model is considered as an animal test for screening anti-
effective in patients with schizophrenia.
psychotic activity of standard and experimental compounds
characterized by D1 and/or D2 antagonist activity [50].
Potential antipsychotics attenuate climbing behavior of mice
4.2. Serotonin receptors evoked by apomorphine which enhances dopaminergic neu-
rotransmission in the mesolimbic system. Cariprazine, orally
An increase in 5-HT1A binding receptors after repeated
administered, potently inhibited apomorphine-induced climb-
(28 days) treatment of cariprazine or aripiprazole was mea-
ing in mice with a median effective dose (ED50) of 0.27 mg/kg
sured in the medial and dorsal prefrontal cortex, which is
[26], which supports cariprazine’s high ability to block D2
shared with atypical antipsychotics [40,41]. In addition, the
receptors in vivo [12].
measured 5-HT1A receptor upregulation in the hippocampal
CA1 and CA3 subregions after cariprazine treatment is
shared with aripiprazole [28] and asenapine only [41].
5.2. Novelty or psychostimulant-induced hypermotility
However, both latter compounds downregulate 5-HT2A
receptors in all the examined forebrain regions but caripra- Cariprazine dose-dependently attenuated novelty-evoked
zine failed to alter that [28]. This lack may be due to the locomotor activity both in mice (ED50 = 0.18 mg/kg) and in
lower in vitro affinity of cariprazine toward 5-HT2A receptors rats (ED50 = 0.11 mg/kg) reaching a plateau at approximately
resulting in insufficient occupancy of these binding sites to 70% inhibition as shown by its sigmoidal fit [26]. Isolation
the level required to induce their changes. This prolong rearing of rats alone or combined with neonatal phencyclidine
action of cariprazine on 5-HT1A receptors might contribute, (PCP) administration causes developmental induction of a
at least in part, to its beneficial therapeutic effects in mini- reproducible hyperactivity in response to placement in a
mizing the incidence of extrapyramidal side effects and in novel arena. This effect is regarded as a marker for striatal
improving cognitive functions in patients with schizophre- dopaminergic hyperactivity akin to positive symptoms of schi-
nia acting indirectly via neocortical glutamate pyramidal zophrenia. Moreover, it is attenuated by several antipsychotic
neurons, where these receptors are located [42]. Serotonin drugs [51–53]. Cariprazine at doses of 0.1 and 0.3 mg/kg
5-HT2A receptors are less likely to contribute to the in vivo attenuated the hyperactivity of rats induced by neonatal PCP
mechanism of cariprazine’s action. and social isolation rearing [54]. Since most typical and

atypical antipsychotics attenuate or block the stimulation
evoked by amphetamine in locomotor activity [55], cariprazine
was tested after oral administration in rats using that test. It
showed blockade of amphetamine-induced hypermotility with
ED50 = 0.12 mg/kg [26]. In glutamatergic models of positive
symptoms of schizophrenia, that is, locomotor activity induced
by MK-801 or PCP, cariprazine demonstrated potent inhibition
against both psychostimulants, MK-801 in mice
(ED50 = 0.049 mg/kg) and PCP in rats (ED50 = 0.09 mg/kg)
[26]. As Leriche et al. [56] demonstrated that MK-801-induced
hyperactivity is very sensitive to D3 receptor antagonist/partial
agonist action, the above effect of cariprazine supports its
ability to block/partially block D3 receptors in vivo.
5.3. Serotonergic activity models in rats
Because of its high affinity toward 5-HT1A receptors and mod-
erate affinity toward 5-HT2A [12], cariprazine was further stu-
died in rat lower lip retraction and mouse DOI-induced head
twitch tests, respectively. Cariprazine induced lower lip retrac-
tion after oral administration of 2 mg/kg and dose-depen-
dently reduced head twitch behavior evoked by DOI,
yielding an ED50 value of 0.27 mg/kg [26]. These finding con-
firm cariprazine agonist/partial agonist 5-HT1A activity and 5-
HT2A antagonist action, respectively.
5.4. Catalepsy
Up to a dose of 85 mg/kg cariprazine did not induce catalepsy
in rats [26], which could reflect its weak propensity toward
extrapyramidal side effects in the clinical-setting. Several
mechanisms may underlie this feature, that is, mixed D3/D2
antagonist activity with D3 preference, partial D2 agonist, and/
or 5-HT1A receptor partial agonist efficacy [12].
5.5. Conditioned avoidance response (CAR)
CAR assay features high construct validity with respect to
efficacy and potency on the positive symptoms of schizophre-
nia [57] and has shown a high degree of predictive validity for
screening typical and atypical antipsychotic activity [58].
Cariprazine dose-dependently inhibited rat CAR in the shuttle
box with ED50 = 0.84 mg/kg [26]. Inhibition of the CAR effect
by cariprazine shows a good correlation with its striatal D2
receptor occupancy [12].
6. Activity of cariprazine in behavioral models of
negative symptoms and cognitive dysfunction
occurring in schizophrenia
Repeated PCP administration appears to produce robust and
enduring effects that are more consistent with the chronic symp-
toms observed in patients with schizophrenia [59]. Chronic PCP
exposure has been associated with lasting neurochemical changes
in the prefrontal cortex, including decreased cerebral blood flow,
glucose utilization, and decreased dopamine neurotransmission
[60,61]. Moreover, subchronic PCP (e.g. 7 days [62]) exposure was
linked to highly localized morphological abnormalities in the brain
regions associated with the pathogenesis of schizophrenia and
EXPERT OPINION ON DRUG DISCOVERY 5
accompanied by attentional impairments [63]. Another model
used in the development of potential antipsychotics constitutes
neonatal treatment of rats with PCP that disrupts neuronal devel-
opment and synaptogenesis and also reproduces many behavioral
features akin to schizophrenia in adult animals such as hyperactiv-
ity to psychostimulants, attenuated sensorimotor gating, and cog-
nitive deficits [64,65]. Furthermore, combining neonatal PCP
administration with subsequent isolation rearing causes additional
attenuation of social interaction [66,67], imitating social withdra-
wal observed in patients. One of the advantages of such afore-
mentioned models is evaluation of behavioral deficits in a drug-
free state because after PCP treatment there is washout period
included, lasting for 1 week or longer. Then, any potentially con-
founding effects on behavior as a result of the PCP present in the
animal are eliminated.
6.1. Novel object recognition paradigm (NOR)
NOR task, a measure of visual recognition memory, disrupted
by PCP is associated with hypodopaminergic dysfunction in
the prefrontal cortex [59]. Cariprazine (0.05 mg/kg) reversed
this impairment, evoking no effects on line crossings confirm-
ing specificity of this action. A dose of 0.1 mg/kg cariprazine
significantly reversed PCP-induced deficits in NOR in spite of
the significant reduction in line crossings. In addition, the
compound had no effects on the total object exploration.
The highest dose tested (0.25 mg/kg) evoked significant seda-
tive effects by attenuating the number of line crossings and
object exploration [62]. In the ‘dual-hit’ model of the disease,
cariprazine (0.03 and 0.3 mg/kg) dose-dependently reversed a
delay-induced impairment in NOR in rats given neonatal PCP
and housed in social isolation [54]. This effect may be due, at
least in part, to cariprazine’s D3 and/or D2 blockade as well as
5-HT1A partial agonist activity [12].
6.2. Executive function models
Patients who suffer from frontal lobe deficiencies can easily
learn and follow individual rules, but have great difficulty
modifying their responses to new rules [68–70]. Patients with
schizophrenia do not adapt normally to changes in their
environments, especially in social and emotional contexts,
and they exhibit an inability to modify responses in testing
situations [71–74]. There are behavioral tasks requiring animals
to show cognitive flexibility, attention, and motivation [59,75].
Usually PCP is used to impair the aforementioned features in
animal models. In reversal learning task, rats maintained at
80–90% free-feeding weight were trained to respond for a
food reward on a fixed ratio schedule of reinforcement, so
that pressing either of the two active levers delivers food
pellets. Once animals had acquired a lever-pressing response,
they were trained to press either the left or the right lever
(only one was active then) for food delivery. The active lever
varied from day-to-day and such training lasted a couple of
weeks. Next, the rats were trained to press either the left or
the right lever for food delivery according to the presence or
absence of a visual cue until they reach ≥90% of the correct
responding. In the reversal learning task, rats are tested for
their ability to abandon a previously learned reward
6 A. WESOŁOWSKA ET AL.
contingency and acquire a new strategy to obtain reward. PCP
in that test impairs the ability of rats to switch learning stra-
tegies in the reversal phase. Cariprazine at doses of 0.1 and
0.25 mg/kg significantly attenuated such PCP impairments
showing efficacy in improving executive function [62]. The
attentional set-shifting task (ASST) employs both relevant
and irrelevant stimuli (e.g. odor and texture) with the help of
which animals are trained to retrieve a food reward. During
separate phases of the task, animals learn to reach an appro-
priate criterion of consecutive correct trials using first an
intradimensional and then an extradimensional shift of atten-
tion which is disturbed (e.g. by PCP). In wild-type mice, car-
iprazine at doses of 0.01 and 0.02 mg/kg significantly reverses
deficits induced by PCP administration, while showing no
activity in D3-receptor knockout mice [76].
6.3. Conditioned freezing response (CFR)
CFR is performed using a two-chamber shuttle box with light
and dark sides and with wire grid floors, separated by an
automated door. Conditioned (light and tone) and uncondi-
tioned (foot shock) stimuli are delivered according to different
protocols. Reduction in freezing following reexposure to the
context or cue may result from altered hippocampal and
amygdala functions [76,77]. Cariprazine given at doses of 0.1
and 0.3 mg/kg did not reverse the CFR deficit in the ‘dual-hit’
model [54], indicating that it lacks the effect on associative
learning in the clinical setting.
6.4. Social interaction
Subchronic treatment of PCP produces significant increases in
avoiding social behavior of rats such as sniffing, following conspe-
cifics, and other interactions. Cariprazine at a dose of 0.05 mg/kg
reversed PCP-induced social behavior deficits in the absence of any
effect on line crossings. Higher doses of the drug (0.1 and 0.25 mg/
kg) produced nonspecific activity in this test due to moderate
sedative effects [62]. In another study [54], the total social interac-
tion was unaffected by cariprazine administered at doses of 0.1
and 0.3 mg/kg. PCP administered at a single dose in mice pro-
duced reduction in social interaction time and social recognition
memory. Cariprazine at doses of 0.01 and 0.02 mg/kg significantly
reversed social recognition/interaction and social recognition
memory impaired by PCP in wild-type mice, but not in D3-receptor
knockout mice [76], confirming that dopamine D3 receptors con-
tribute to the action of cariprazine.
6.5. Spatial working memory models
PCP given at a single dose evoked significant impairments in
the performance of mice in a delayed alternation test per-
formed in a T-maze. Cariprazine in the dose range of 0.005–
0.2 mg/kg significantly reversed PCP-induced deficits in wild-
type mice, but not in D3-receptor knockout mice [76].
Similarly, in water-labyrinth learning performance, when an
amnestic drug, scopolamine, was used in order to induce
deficits in memory, cariprazine in the dose range of 0.02–
0.075 mg/kg significantly reversed the amnestic effects in
rats. Lower (0.01 mg/kg) and higher doses (0.15–0.3 mg/kg)
of the drug did not evoke significant responses [26].
Cariprazine’s unique receptor profile may support its procogni-
tive activity observed in the most described paradigms, in parti-
cular antagonism at D3 receptors. This, in combination with
appreciable affinity toward D2 receptors, high affinity toward 5-
HT2B, and moderate affinity toward 5-HT1A binding sites as well as
partial agonist/antagonist action toward these receptors may help
to explain cariprazine’s procognitive effects in preclinical models.
7. Activity of cariprazine in behavioral models of
anxiety and depression
7.1. Elevated plus-maze (EPM)
EPM is a behavioral test that is widely employed to assess
anxiety-like behaviors in rodents. This test is based on
approach/avoidance conflict, with rodents perceived as ‘less
anxious’ being more willing to explore the brighter, open, and
elevated arms of the apparatus as opposed to remaining in
the darkened and enclosed arms. Measures of the time spent
in open arms and the number of open arm entries serve as an
index of anxiety-like behavior. Cariprazine in the dose range of
0.005–0.15 mg/kg was tested in EPM in wild-type mice having
no anxiolytic-like action. Only at the highest doses of 0.08 and
0.15 mg/kg, the drug decreased the number of open and
closed arm entries showing sedative action [76].
7.2. Chronic mild stress (CMS)
Anhedonia is a core component of negative symptoms in
schizophrenia and one of the most challenging-to-treat symp-
toms associated with depression [78,79]. A rodent model that
mimics anhedonic symptoms and the lack/decrease in the
ability of such patients to experience pleasure is CMS. In this
model, animals (usually rats or mice) are chronically exposed
to a constant bombardment of unpredictable and different
microstressors (e.g. forced swim, cage tilt, light/dark distur-
bance, no/wet bedding, odor, and strobe light), resulting in
the development of behavioral changes, including decreased
response to rewards. A rodent version of rewards is access to a
highly preferred sweet solution, or to a choice between a
sweet solution (sucrose) and plain water. Consumption of, or
preference for, the sweet reward decreases over several weeks
of exposure to stressors, but can be restored to normal levels
by chronic treatment with antidepressant drugs from many
therapeutic classes, acting by different intracellular and sys-
temic mechanisms [79]. CMS, sometimes also called chronic
unpredictable/varied stress, is considered one of the best-
validated animal models available to test novel compound
treatments for anhedonic-like symptoms [80].
Repeated treatment (5 weeks) with cariprazine in the dose
range of 0.01–1 mg/kg reversed the CMS-induced reduction in
sucrose consumption in rats reaching an ED50 dose of
0.052 mg/kg. Only the lowest (0.01 mg/kg) and the highest
(1 mg/kg) doses of cariprazine did not statistically reverse
anhedonia in rats, possibly due to insufficient levels of D2
and D3 receptors’ engagement or sedative effects, respec-
tively. This reversal was similar to that observed after
 EXPERT OPINION ON DRUG DISCOVERY 7

treatment with the standard antidepressant medication such 9. Conclusion

as imipramine (10 mg/kg) or aripiprazole (ED50 = 4.4 mg/kg)
Cariprazine is an antipsychotic medication that received
[81]. Chronic administration (21–22 days) with cariprazine at
approval from the US FDA in September 2015 for the acute
doses of 0.2 and 0.4 mg/kg in mice exposed to chronic unpre-
treatment of manic or mixed episodes associated with bipolar
dictable stress (CUS) statistically reversed the attenuation of
I disorder and the treatment of schizophrenia in adults. It has
sucrose consumption in a novel environment, producing an
also received approval from the European Medicines Agency
antianhedonic-like effect on the same level as imipramine
in June 2017 for the treatment of schizophrenia in adult
(20 mg/kg) and aripiprazole (5 mg/kg). Interestingly, the
patients. It is formulated into capsules/hard capsules of differ-
same activity of cariprazine was not observed in D3-receptor
ent strengthens and administered orally, typically once daily at
knockout mice. Furthermore, the same authors also demon-
the same time of the day with or without food. Cariprazine
strated anxiolytic-like activity of cariprazine (0.2 and 0.4 mg/
and its major active metabolites (DCAR and DDCAR) are highly
kg) after repeated administration (24–25 days) to wild-type
bound (>90%) to plasma proteins which is an important factor
mice, but not D3-receptor knockout mice, exposed to CUS by
to be considered when treating comorbidities. The half-life of
significantly reducing latency to drink (diluted sweetened con-
terminal disposition of cariprazine is 5–6 days and elimination
densed milk) in the novelty-induced hypophagia test.
of active DDCAR is prolonged even to 2–3 weeks in both
Cariprazine produced the same level of activity as aripiprazole
healthy volunteers and patients with schizophrenic patients.
(1 and 5 mg/kg) in wild-type mice [82]. The above findings
Cariprazine is metabolized by the CYP3A4 pathway, and to a
show a clear involvement of D3 receptors in both the anxioly-
lesser extent, by CYP2D6. Hence, it should not be coadminis-
tic- and antidepressant-like activity of cariprazine. Moreover,
tered with CYP3A4 inducers or inhibitors. It is also not recom-
Duric et al. [82] observed that aripiprazole induced increases in
mended in patients with severe renal or hepatic impairment.
the total fluid consumption, which could be due to polydipsia
In patients with schizophrenia, cariprazine is recommended in
and/or polyuria, potential side effects of some antipsychotic
the dose range of 1.5–6 mg/day. The efficacy of cariprazine in
drugs [83,84]. In this regard, cariprazine had a more specific
acute schizophrenia was established in, three positive 6 week,
effect independent of changes in the overall liquid
Phase II/III, randomized controlled clinical trials which demon-
consumption.
strated improvement over placebo-treated patients [83].
Additionally, in 26-week, double-blind, randomized study in
8. Antimanic and antiabuse activities of cariprazine nonelderly patients with schizophrenia, and predominant
negative symptoms, cariprazine is superior to risperidone on
Intracerebroventricular single injection of ouabain is the
both the primary and the key secondary outcomes [83]. The
only available model of bipolar disorder and is among
most commonly encountered adverse effects are extrapyrami-
the best characterized rodent models of mania sensitive
dal symptoms and akathisia. Changes in body weight (small),
to lithium and other antimanic agents. Ouabain increases
glucose, lipid, and prolactin levels as well as in QT interval are
dopamine levels in the synapse and induces hyperactivity
not clinically meaningful.
measured in the open field test. It can also alter intracel-
Cariprazine exhibits the highest affinity toward dopamine
lular signaling pathways such as Akt-GSK-3 and D2 recep-
D3 (pKi = 10.7) and D2 (pKi = 9.31) receptors, followed by
tor/β-arrestin 2 [85,86]. Cariprazine (0.06–1 mg/kg), acting
serotonin 5-HT2B (pKi = 9.24) and 5-HT1A (pKi = 8.59). It has
as a D2 receptor partial agonist, attenuated hyperlocomo-
negligible affinity toward many other receptors, ion channels,
tor activity induced by ouabain. Subchronic (7 days)
and enzymes [12]. Interestingly, cariprazine does not share
administration of cariprazine at a sedative dose of 1 mg/
with other atypical antipsychotic drugs their higher affinity
kg statistically reduced an ouabain-evoked increase in
toward 5-HT2A (pKi = 7.73) over D2 receptors. But, its unique-
locomotor activity [86]. Although the above effect mea-
ness depends on having a higher potency for the D3 receptors
sured in animals appears to be unspecific, the results
than dopamine itself. Cariprazine demonstrated approximately
obtained from a recent meta-analysis of antimanic treat-
10-fold lower affinity toward histamine H1 and 5-HT2C recep-
ments showed that cariprazine demonstrates robust clinical
tors than for example, aripiprazole. Therefore, it is hypothe-
efficacy in patients with acute mania associated with bipo-
sized that cariprazine has low propensity toward causing
lar disorder [87].
sedation and body weight gain, side effects commonly asso-
Behavioral features of addiction including drug intake and
ciated with high H1 and 5-HT2C antagonist activity. Functional
relapse are amenable to modeling in animals. Rodents readily
in vitro studies found that cariprazine exhibits biased agonist
self-administer the same psychoactive drugs as humans
activity against D3/D2 receptors (depending on the assay/sig-
including cocaine, and following a period of abstinence, rein-
naling system involved), complete antagonistic activity toward
state their drug seeking when exposed to the same factors
5-HT2B, and partial agonist activity against 5-HT1A. Cariprazine
that put humans at risk of relapse. One of such paradigms is
has lower intrinsic activity at D2 receptors than aripiprazole
the cocaine self-administration model that mimics the situa-
which may translate into a better clinical profile because a bit
tion of abusers. Cariprazine reduced the rewarding effect of
higher agonist activity of aripiprazole seems to be responsible
cocaine (0.17 mg/kg) and attenuated relapse to cocaine-seek-
for its activation, agitation, and akathisia in some patients. In
ing with an ED50 value of 0.2 mg/kg in rats [88]. The antiabuse
this respect, cariprazine is more comparable to brexpiprazole
effect may enhance the therapeutic value of cariprazine as an
[90]. Whether the 5-HT2B receptor antagonism of cariprazine,
antipsychotic drug since drug abuse is a frequent comorbidity
in addition to its D3, D2, and 5-HT1A affinities, contributes to its
of both schizophrenia and mania.
8 A. WESOŁOWSKA ET AL.

antipsychotic activity and the side effect profile is presently Table 1. Summary of some literature data supporting the activity of cariprazine
in animal models of neurological disorders.
unclear. This explanation may be particularly important and
interesting given the recent data demonstrating that the Behavioral paradigm ED50/dose range efficacy
blockade of 5-HT2B receptors reduces significantly mesoac- Schizophrenia
Positive symptoms
cumbal dopamine transmission [91], whereas 5-HT2B receptor Apomorphine-induced 0.27 mg/kg in mice
deficiency in mice induces a wide spectrum of schizophrenic- climbing
like behavioral and psychopharmacological phenotypes [92]. DOI-induced head twitches 0.27 mg/kg in rats
Novelty-induced locomotor 0.18 mg/kg in mice
Clinical consequences of relatively low affinity of cariprazine hyperactivity 0.11 mg/kg in rats
toward 5-HT2A receptors are also unknown yet. Locomotor hyperactivity 0.12 mg/kg inhibited amphetamine effect in
Behavioral studies demonstrated cariprazine’s effectiveness rats
0.09 mg/kg inhibited PCP effect in rats
in different animal models of schizophrenia, mimic positive, 0.049 mg/kg inhibited MK-801 effect in mice
negative, and/or cognitive symptoms. It inhibited apomor- Conditioned avoidance 0.84 mg/kg in rats
phine-induced climbing behavior, CAR, and attenuated psy- response
Negative symptoms and
chostimulant or novelty-induced increases in locomotor cognitive impairments
activity (rodent models predictive of antipsychotic activity). Novel object recognition 0.05 and 0.1 mg/kg reversed PCP deficits in
In tests predictive of negative (social interaction), cognitive (NOR) rats
‘Dual-hit’ model in rats 0.1 and 0.3 mg/kg inhibited hyperactivity
(water-labyrinth learning performance and NOR), and execu- 0.03 and 0.3 mg/kg reversed PCP deficits in
tive functions (ASST and reversal learning task), cariprazine NOR
ameliorated subchronic or neonatal PCP and isolation-induced 0.1 and 0.3 mg/kg were inactive in
conditioned freezing response
deficits in rats. In animal models of anxiety and depression, 0.1 and 0.3 mg/kg were inactive in social
repeated cariprazine evoked anxiolytic- and antidepressant- interaction
like effects, in the novelty-induced hypophagia test and CMS Social interaction 0.05 mg/kg reversed PCP deficits in rats
0.01 and 0.02 mg/kg reversed PCP deficits in
model, respectively (Table 1). mice
Long-term cariprazine induced selective adaptive changes 0.01 and 0.02 mg/kg were inactive in D3-
in dopaminergic, serotonergic, and glutamatergic receptors in receptor knockout mice
Reversal learning task 0.1 and 0.25 mg/kg attenuated PCP deficits in
various rat brain regions. It produced regional and dose- rats
dependent upregulation of D2 and D4 receptor subtypes simi- Attentional set-shifting task 0.01 and 0.02 mg/kg reversed PCP deficits in
lar to other atypical antipsychotics. Hippocampal D4 receptors mice
T-maze 0.005–0.2 mg/kg reversed PCP deficits in mice
may constitute common targets that mediate the molecular 0.005–0.2 mg/kg were inactive in D3-receptor
actions of cariprazine, acting together with hippocampal D2 knockout mice
receptors to improve impaired emotional behavior that is Water-labyrinth learning 0.02–0.075 mg/kg reversed scopolamine
performance deficits in rats
commonly associated with psychosis. Additionally, cariprazine Anxiety
was unique in upregulating D3 receptors, which has not been Elevated plus-maze 0.005–0.15 mg/kg were inactive in mice
seen with other antipsychotics. The clinical consequences of Novelty-induced hypophagia 0.2 and 0.4 mg/kg reduced latency to drink in
mice
such a mechanism for patients are unknown, but preclinical 0.2 and 0.4 mg/kg were inactive in D3-
experiments suggest that such an action could be antidepres- receptor knockout mice
sant, anxiolytic, procognitive, active on negative symptoms of Depression
Chronic mild/unpredictable 0.052 mg/kg induced antianhedonic effect in
schizophrenia, and even be helpful in stimulant abuse stress rats
[26,76,80,88,90]. Action at 5-HT1A receptors is a mechanism 0.2 and 0.4 mg/kg induced antianhedonic
thought to enhance the neurochemical and behavioral effects effect in mice
0.2 and 0.4 mg/kg were inactive in D3-
of antidepressant drugs (e.g. selective serotonin reuptake inhi- receptor knockout mice
bitors) [93]. Activity toward glutamate NMDA and AMPA Antimania activity 0.06–1 mg/kg attenuated ouabain
receptors support cariprazine’s ability to improve psychotic hyperactivity in rats
Addiction
and cognitive symptoms visible, among others, through Cocaine self-administration 0.17 mg/kg reduced the rewarding effect in
restoring PCP-induced deficits in glutamatergic neurotrans- rats
mission. Both latter mechanisms are also responsible for mini- 0.2 mg/kg attenuated relapse to cocaine-
seeking in rats
mal extrapyramidal effects seen during cariprazine therapy. Side effects
The clinical consequences of the lack of 5-HT2A receptor action Catalepsy up to 85 mg/kg was inactive in rats
are not established yet. Summing up, the unique actions of Serotonergic syndrome 2 mg/kg induced lower lip retraction in rats
Sedative effect 0.1, 0.25, 1 mg/kg in rats
cariprazine on dopamine D3 receptors, combined with its 0.08 and 0.15 mg/kg in mice
effects on serotonin and glutamate receptor subtypes, may
confer the clinical benefits, safety, and tolerability of this novel
medicine in schizophrenia and bipolar mania.
metabolic side effects. In addition, the available compounds
show limited effect in the domains of negative and cognitive
10. Expert opinion symptoms. Owing to its unique pharmacodynamic profile,
Atypical antipsychotics are considered effective therapeutic cariprazine does not appear to be particularly associated
options in the treatment of schizophrenia, but they are with metabolic issues, increase in prolactin or QTc prolonga-
encumbered by a number of adverse effects, including tion, but extrapyramidal side effects and akathisia are more

common. Cariprazine shares more similarities with the newer
antipsychotics such as the so-called dopamine stabilizers (e.g.
aripiprazole and brexpiprazole), thanks to partial agonist
activity at D2 receptors, which translates into the stabilization
of dopaminergic neurotransmission in appropriate brain
regions. An already-crowded armamentarium of therapeutic
options for the treatment of acute schizophrenia makes pro-
spects of success for cariprazine difficult to achieve but not
impossible. What elements of its activity should help in
achieving such success? For sure, they are not its effective-
ness, tolerability, or favorable metabolic profile, but (i) car-
iprazine’s extra ability to improve negative symptoms, (ii) its
ability to be particularly useful in young patients with a
relatively short duration of the disease, (iii) cariprazine’s abil-
ity to decrease substance abuse, and/or (iv) its ability to
maintain efficacy in cases of missed dose. Meta-analysis as
well as a randomized placebo-controlled, double-blind trial
showed that patients receiving cariprazine demonstrated
greater improvement in prominent negative symptoms com-
pared with patients receiving placebo or risperidone, in func-
tioning, particularly with regard to self-care, interpersonal
relationships, and socially useful activities [94,95]. Therefore,
cariprazine may be the treatment of choice for patients who
have shown improvement in positive symptoms but continue
to have disabling negative symptoms [96]. The effectiveness
of cariprazine in various animal models of learning and
memory, cognitive, and executive functions [54,62,76] sup-
ports its potential clinical advantage in treating cognitive
deficits in patients with schizophrenia. In the rodent and
human studies, cariprazine’s superior improvement in cogni-
tive and social impairments was attributed to its activity at
D3 receptors. Moreover, in those aspects of efficacy, the
active doses of cariprazine used in animal studies correlate
with the dose range proposed in humans.
Psychostimulant abuse is frequently comorbid in patients
with schizophrenia, especially young people, contributing to
worsening the disease and increased morbidity and mortality.
Cariprazine demonstrated the reduction in substance use and
relapse prevention against cocaine rewarding effect in rodents
[88], which can be attributed to its D2 receptor partial agonist
activity. Whether cariprazine’s antiabuse potential, detected in
rat's model, can be extrapolated to humans remains to be
studied, but it might provide greater insights into this topic.
The aforementioned meta-regression data further refined
cariprazine’s clinical profile, suggesting that the medicine is
particularly useful in young patients with a relatively short
duration of the disease [95]. As epidemiologic data show
psychotic symptoms usually emerge in men in their late
teens and early 20s and in women in their mid-20s to
early 30s.
Cariprazine has a half-life of 2–4 days with an active meta-
bolite DDCAR that has a terminal half-life of 2–3 weeks and
systemic exposure to it several times higher than that of the
parent compound [3–5]. It means that the effective dose
needs to be increased for many weeks to get to the steady
state and clinicians could overshoot the ideal dose. However,
upon stopping cariprazine treatment, it will be many weeks
before the active molecules are washed out, which could be a
potential advantage for patients with schizophrenia
EXPERT OPINION ON DRUG DISCOVERY 9
characterized by poor compliance. Thus, missing a dose here
and there would not have a ruinous effect on relapse, which is
yet to be proven in a clinical setting [90].
Cariprazine is unique among antipsychotic drugs in terms
of having a higher potency for the D3 receptor than dopamine
itself and antagonist/partial agonist activity [12]. Although the
consequences of such an action for patients with schizophre-
nia are unknown yet, preclinical findings indicate that such a
mechanism can be responsible for, among others, antidepres-
sant/anxiolytic effects. Such data may support cariprazine’s
utility in the treatment of major depressive disorder (MDD),
at least as adjunctive therapy, which has been confirmed by
randomized, double-blind, placebo-controlled, flexible-dose
study in adult inadequate responders to antidepressant ther-
apy [97]. Cariprazine’s partial agonist activity at 5-HT1A recep-
tors may confer additional benefits in the treatment of
depression and anxiety, since these receptors have been
involved in the etiology of both disorders. The ability of car-
iprazine to evoke potential antidepressant and anxiolytic activ-
ity after long-term treatment in rodent models of depression
and anxiety [81,82] adds further support for its actions.
Nonetheless, further characterization of the comparative
effectiveness of cariprazine awaits the conduct of additional
and extended clinical trials to evaluate its procognitive and
antidepressant/anxiolytic effects in patients with schizophre-
nia and other psychiatric disorders characterized by such def-
icits (e.g. MDD, Alzheimer’s disease, and ADHD). Only clinical
findings may further translate the unique preclinical profile of
cariprazine into benefits.
Funding
The authors are supported by funds for their statutory activity from the
Jagiellonian University Medical College (K/ZDS/006133).
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties. Peer
reviewers on this manuscript have no relevant financial or other relation-
ships to disclose.
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