Perspectives in Psychiatric Care ISSN 0031-5990

Cariprazine for the Treatment of Bipolar Disorder

Lillian Jan Findlay, PhD, Peggy L. El-Mallakh, PhD, and Rif S. El-Mallakh, MD
Lillian Jan Findlay, PhD, is Assistant Professor, and Coordinator, Psychiatric Mental Health Academic Program, School of Nursing, University of
Kentucky, Lexington, Kentucky, USA; Peggy L. El-Mallakh, PhD, is Assistant Professor, School of Nursing, University of Kentucky, Lexington,
Kentucky, USA; and Rif S. El-Mallakh, MD, Director, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University
of Louisville School of Medicine, Louisville, Kentucky, USA

Search terms: PURPOSE: To review the data regarding a new antipsychotic, cariprazine.
Bipolar depression, bipolar disorder, CONCLUSIONS: Cariprazine is a dopamine D3, D2 partial agonist, with
cariprazine, dopamine D3 receptor, dopamine greater affinity to D3. It has been examined for schizophrenia, bipolar mania,
D2 receptor, mania
bipolar depression, and unipolar depression. It has demonstrated efficacy in
Author contact: schizophrenia and mania, and has recently been approved by the U.S. Food and
rselma01@louisville.edu, with a copy to the Drug Administration. However, it has a more inconsistent effect in depression, both
Editor: gpearson@uchc.edu unipolar and bipolar. Adverse effects include extrapyramidal symptoms, akathisia,
and gastrointestinal distress.
Conflict of Interest Statement
Dr. Rif S. El-Mallakh has grant funding from
PRACTICE IMPLICATIONS: Cariprazine will be a promising addition in the
Merck, Psychnostics, and Teva. He is a speaker treatment of patients with acute mania and schizophrenia.
for Allergan, AstraZeneca, Merck, Lundbeck,
Otsuka, Sunovion, and Takeda. The other
authors do not have any conflicts of interest to
declare. This work was not funded by any
extramural source.

First Received July 28, 2015; Final Revision

received November 26, 2015; Accepted for
publication December 21, 2015

doi: 10.1111/ppc.12150

Cariprazine is a new, novel antipsychotic medication that
has currently received approval by the U.S. Food and Drug
Administration (FDA) for use in both bipolar disorder
and schizophrenia (http://www.allergan.com/news/news/
thomson-reuters/allergan-and-gedeon-richter-plc-receive-
fda-approv). It is a piprazine derivative that was developed
by the Hungarian company Gedeon-Richter. Cariprazine is
a well-studied, promising agent that is expected to become
widely utilized. This paper reviews the basic and clinical data
available for cariprazine.
Gedeon-Richter scientists were attempting to isolate a
dopamine D2 and D3 antagonist, when they ran into
a problem—their preparation had a persistent impurity
(Ágainé-Csongor et al., 2012). To be able to remove the
impurity, they had to identify it. This compound, trans-N-[4-
[2-[4-(2,3-dichlorophenyl) piperazin-1-yl]ethyl]cyclohexyl]
-N ,N -dimethylurea hydrochloride, was given the working
name of “2m” and subsequently registered as RGH-188 or
cariprazine. Preclinical studies suggested that this impurity
was a more promising chemical than the original targets
of their research (Ágainé-Csongor et al., 2012). Subsequent
development led to the current FDA approval.
The drug’s developers had a specific intent to create a drug
that was a partial agonist, and had greater affinity for the
D3 receptor (Ágainé-Csongor et al., 2012). In this sense, the
creation of cariprazine is the result of an effort to create a drug
that has cariprazine properties. To understand why that effort
was undertaken, and why cariprazine may offer some clinical
advantages to patients receiving it, one must first understand
the reasoning behind the use of partial agonists and the role
of D3 antagonism.
Why a Partial Agonist?
It is clear that D2 blockade reduces psychosis (Madras, 2013;
Seeman, 2002). It is also clear that only about 65% D2
receptor occupancy is required to achieve the antipsychotic
effect (Madras, 2013; Seeman, 2002). However, we generally
use antipsychotic medications, particularly first-generation
agents, to achieve nearly 90% receptor occupancy (Kapur
et al., 1997). Most dopamine-mediated adverse consequences
of antipsychotics occur when receptor occupancy exceeds
80% (Kapur et al., 1996). This occurs in animals (Johnson
et al., 2014) and humans (Horacek et al., 2006; Nordstrom

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Cariprazine for the Treatment of Bipolar Disorder
et al., 1993). Avoiding dopamine-related side effects generally
means utilizing the minimal antipsychotic dose, but that
usually results in reduced confidence regarding maximizing
efficacy, particularly since the minimal antipsychotic dose is
frequently less that the recommended dose (Leucht et al.,
2014).
High-affinity partial agonists solve this problem. When
such a drug is administered at doses that approach
95% receptor occupancy, the partial activation of the D2
receptor results in an apparent lower level of blockade. With
aripiprazole and brexpiprazole, which are the only other
available partial agonist antipsychotics, the partial activation
of D2 receptors to approximately 25–30% of the maximal
dopamine signal means that maximal occupation of the
D2 receptors results in an ongoing dopamine signal that is
25–30% of the maximal possible signal (Burris et al., 2002;
Gründer, Kungel, Ebrecht, Göröcs, & Modell, 2006). This is
actually important, since the dopamine system maintains a
tonic level of release (Sheynikhovich, Otani, & Arleo, 2011),
which is approximately 20–25% of the maximal signal. That
number is confirmed by the observation that aripiprazole
generally slightly reduces prolactin release at doses that
achieve 95% receptor occupancy (Cosi et al., 2006; Yokoi
et al., 2002). In other words, a clinician can administer a
partial D2 agonist at high doses and still avoid full dopamine
blockade, and thus reduce dopamine blockade-related side
effects such as parkinsonism, elevated prolactin, and possibly
tardive dyskinesia.
D3
D3 has limited expression in the brain, with the highest
density in the nucleus accumbens (NA) and olfactory
tubercle (Bouthenet et al., 1991; Diaz et al., 1994; Ridray
et al., 1998). Antipsychotics frequently block D3 (Sokoloff,
Giros, Martres, Bouthenet, & Schwartz, 1990; Sokoloff
et al., 1995), and a genetic variant of this receptor has
been associated with risk of developing tardive dyskinesia
secondary to first-generation antipsychotics (Bakker, van
Harten, & van Os, 2006), suggesting that it may play a role
in the therapeutic benefit, or the adverse consequences, of
antipsychotics.
Preclinical work reveals that overexpression of D3 reduces
motivation in mice, whereas its blockade improves cognition
and reduces hyperactivity in rats (Barth et al., 2013). These
are symptoms that may be targets in both bipolar illness
and the negative symptoms of schizophrenia (Fountoulakis,
Kelsoe, & Akiskal, 2012; Gross, Wicke, & Drescher, 2013).
True to these predictions, cariprazine has demonstrated
efficacy in animal models that examine cognition (Gyertyán
et al., 2011; Zimnisky et al., 2013), depression (Papp et al.,
2014), and mania (Gao et al., 2015).
2
Clinical Research Program for Cariprazine
According to ClinicalTrials.gov, cariprazine has been or is
being investigated in 18 clinical trials. Fourteen of these
have been completed, and nine are intended to study mood
disorders (Table 1). While the majority of these studies have
not been published, we will review the information that is
available.
Pharmacodynamics and Pharmacokinetics
Cariprazine has very high affinity to the human D3 and
D2 receptors, as well as the serotonin 5HT2B receptor
(Table 2). It also has high affinity to other serotonin receptors
such as 5HT1A and 5HT2A (Table 2). This profile is similar
to aripiprazole, except that the affinity for D3 is greater than
for D2, and is so high that extremely small doses are sufficient
to get maximal D3 occupancy (Kiss et al., 2010). Doses of
1 mg daily are sufficient to achieve the therapeutic level
of over 65% receptor occupancy (Laszlovsky et al., 2007).
Doses of 1.5 mg daily achieve 69–75% receptor occupancy
in subjects with schizophrenia (Potkin et al., 2009).
The half-life of cariprazine is approximately 2–6 days
(Kapás et al., 2008; Pásztor Mészáros et al., 2007). Cmax
is reached within 3–4 hr of an oral dose. It breaks down
into two active metabolites that are less well-characterized:
desmethyl-cariprazine and didesmethyl-cariprazine (Pásztor
Mészáros, Agai-Csongor, & Kapaś, 2008), which also have
long half-lives (Kapás et al., 2008; Pásztor Mészáros et al.,
2007). Steady state is reached in about one week for
cariprazine, and over one month, if one considers the
metabolites. Cariprazine is metabolized predominately by
CYP450 3A4, and to a lesser extent by CYP450 2D6
(Kirschner et al., 2008). The dose ranges tested include
3–12 mg daily, and the drug appears safe in that dose range.
Efficacy in Schizophrenia
Six controlled studies have been performed with cariprazine
in patients with acute psychosis secondary to schizophrenia;
two were acute phase II and three were acute phase III
(Citrome, 2013a), and one was a phase III maintenance study.
The majority of this work has yet to be published in peer-
reviewed journals.
A dose-finding phase II study was performed in 65 sites
in the United States (38%), India (22%), Russia (22%),
Ukraine (16%), and Malaysia (3%) and randomized 732
patients equally to one of five following arms: cariprazine
1.5 mg/day, cariprazine 3.0 mg/day, cariprazine 4.5 mg/day,
placebo (or negative control), and risperidone 4.0 mg/day
(a positive control; Durgam, Starace, et al., 2014). Despite
a high dropout rate (only 64% completed the study),
all active medication arms separated from placebo. There
appeared to be a dose-related increase in efficacy (−7.6,
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 Cariprazine for the Treatment of Bipolar Disorder

Table 1. Mood Disorder Studies Examining Cariprazine Registered With ClinicalTrials.gov

(https://clinicaltrials.gov/ct2/results?term=cariprazine&Search=Search)

Study Number Indication Status Outcome Reference

NCT00488618 Mania (Phase 2) Completed Positive Durgam, Nasrallah, et al. (2014)

NCT01058096 Mania (Phase 3) Completed Not published Citrome (2013b)
NCT01058668 Mania (Phase 3) Completed Not published Citrome (2013b)
NCT00852202 Bipolar depression (phase 2) Completed Negative, not published Forest Laboratories, Inc. (2010)
NCT01396447 Bipolar depression (phase 2) Completed Not published
NCT01059539 Bipolar open, long-term Completed NA
NCT01469377 Major depression adjunct (phase 2) Completed Not published
NCT01838876 Long-term major depression (phase 3) Ongoing NA
NCT01715805 Major depression adjunct (phase 3) Ongoing NA

−8.8, −10.4 points of improvement in the Positive and Table 2. The Affinity of Cariprazine to Dopamine and Serotonin
Negative Syndrome Scale [PANSS] at week 6, respectively, for Receptors (Derived from 30)
cariprazine 1.5 mg/day, cariprazine 3.0 mg/day, cariprazine Receptor Ki (nM) Action at receptor
4.5 mg/day) but the study was not powered sufficiently
to determine if this is accurate (Durgam, Starace, et al., D2 0.5 Partial agonist
2014). An earlier phase II was presented in poster format D3 0.085 Partial agonist
5HT1A 3.0 Partial agonist
(Litman, Papadakis, Durgam, & Xie, 2008) but never
5HT2A 19.0 Antagonist
published and was summarized by Citrome (2013a). This 5HT2B 0.58 Antagonist
was a three-arm study, which randomized 392 patients with 5HT2C 134 Antagonist
acute exacerbation of schizophrenia to placebo, low-dose 5HT7 111 Antagonist
cariprazine (1.5–4.5 mg/day), and high-dose cariprazine (6– H1 23 Antagonist
12 mg/day), and was performed in 34 sites in the United
Please note that the Ki for the endogenous ligand (the neurotransmitter)
States (Citrome, 2013a; Litman et al., 2008). The low-dose is 1.0 for all receptors; values <1.0 mean that the affinity is higher than
arm was minimally superior to placebo, but the overall effect for the neurotransmitter, values >1.0 mean that the affinity is lower than
was essentially not significant. for the neurotransmitter.
Three acute phase III trials were performed. Two were
additional 72 weeks (Durgam, Nasrallah, et al., 2014). There
made available in a press release (Forest Laboratories, Inc.,
were a total of 25 relapses (24.8%) in the cariprazine group,
2012a). In one study, 446 patients with schizophrenia were
compared with 47 relapses (47.5%) in the placebo group.
randomly assigned to placebo, 3–6 (average dose 4.2) mg/day,
This is a 55% reduction in the risk of relapse if a patient
or 6–9 (average dose 6.6) mg/day for 6 weeks. Both dose arms
remains on cariprazine (hazard ratio for placebo = 0.45, 95%
were significantly better than placebo, with a difference from
CI [0.28, 0.73], p = .0010; Durgam, Nasrallah, et al., 2014).
placebo of –6.8 points for the low-dose arm, and –9.9 for the
high-dose arm (Zukin et al., 2012).
Efficacy in Bipolar Illness
In a second international phase III study, 617 patients with
acute psychosis secondary to schizophrenia were randomly Three randomized controlled trials have been conducted to
assigned to receive cariprazine low dose (3 mg/day), high measure the effect of cariprazine on manic symptoms in acute
dose (6 mg/day), aripiprazole (10 mg/day), or placebo for mania or mixed episodes (Citrome, 2013a; Durgam et al.,
6 weeks in a double-blind fashion. Patients in all active 2015). Durgam et al. (2015) report that a phase II study
arms were significantly more improved than placebo-treated randomized 238 adults to either a flexible-dose cariprazine
patients at the end of the study (Cutler et al., 2015). group or placebo. Cariprazine doses ranged from 3 to 12
The third and largest acute phase III trial compared mg/day. The final dose for 66.1% of participants was 12
placebo and flexible dose of 3–9 mg of cariprazine. The study mg/day; 4.2% were treated with 3 mg/day, 12.7% were treated
has been completed, but we were unable to find details of the with 6 mg/day, and 16.9% were treated with 9 mg/day, with
results (ClinicalTrials.gov, 2015). an average daily dose of 8.8 mg/day (Durgam et al., 2015).
A long-term relapse prevention trial randomized Findings from this study indicated that the cariprazine
200 patients with schizophrenia, who were stabilized on group had significant improvements on all items of the
cariprazine for 3 months, to stay on 3–9 mg/day (n = 101) of Young Mania Rating Scale (YMRS) compared with placebo
cariprazine, or placebo (n = 99), and followed for up to an between baseline and week 3 of the study, with an

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Cariprazine for the Treatment of Bipolar Disorder
adjusted mean difference of –6.12. A significantly greater
percentage of cariprazine-treated participants met criteria
for response (defined as at least 50% improvement), as
measured with the YMRS, compared with placebo (48% vs.
25%; Durgam et al., 2015). Similarly, a significantly greater
percentage of cariprazine-treated participants met criteria
for remission compared with placebo (42% vs. 23%, defined
as a YMRS score <12). Furthermore, statistically significant
improvements were seen in the cariprazine group on the
PANSS (–3.6) and the Clinical Global Impressions—Severity
(CGI-S) scale (–0.8). No significant differences were seen
between the cariprazine group and placebo for total scores of
the Montgomery-Asberg Depression Rating Scale (MADRS).
Dropout rates in this study were considerable; 61.9% (n = 73)
of the placebo group and 63.6% (n = 75) completed the study
(Durgam et al., 2015).
A phase III trial randomized 312 adults with acute or
mixed mania to either a flexible-dose cariprazine group or
placebo. This study design was very similar to the phase
II trial discussed, and included a 4- to 7-day washout
and screening period during inpatient hospitalization and
a minimum of 14 days of treatment. Findings from this
study indicated that symptoms rated on the YMRS were
significantly reduced in the cariprazine group compared with
placebo. Citrome (2013b) reports that responders on the
YMRS were 59% for cariprazine, and remitters were 52%
for cariprazine. In comparison, YMRS responders were 44%
for placebo, and remitters were 35% for placebo. The least-
squares mean reduction in the YMRS scores was –4.3 for the
cariprazine group (Citrome, 2013b).
A second phase III trial randomized 497 patients with
mania to a low-dose arm (3–6 mg/day), high-dose arm
(6–12 mg/day), or placebo for 3 weeks. Both the low-dose
arm (–6.1 points) and high-dose arm (–5.9 points) improved
significantly compared with placebo (p < .001; Citrome,
2013b).
A press release reported a negative outcome in a phase
II study of 233 depressed subjects with bipolar I illness
performed in the United States (Forest Laboratories, Inc.,
2010). There was a very low-dose arm (0.25–0.75 mg/day),
low-dose arm (1.5–3.0 mg/day), and placebo. While patients
receiving the higher dose of cariprazine improved, the
overall effect was not statistically different from placebo
(Forest Laboratories, Inc., 2010). A subsequent phase IIb
study examined 584 depressed patients with bipolar disorder
treated for 8 weeks with cariprazine 0.75, 1.5, and 3.0 mg/day
or placebo (Forest Laboratories, Inc., 2014a). The group
receiving 1.5 mg of cariprazine improved significantly but
transiently at week 6 (four-point improvement on MADRS,
p = .003). This phenomenon of a transient improvement was
also seen with aripiprazole in bipolar depression (Thase et al.,
2008) and may be a reflection of a therapeutic window in a
long half-life drug.
4
Longer-term treatment of subjects with bipolar I illness
was investigated in an open, 16-week study that followed 402
patients. Two thirds of the patients (63%) were in remission
by the end of the study, dropping from a moderately manic
state with a YMRS score of 26.1 to an average of 10.9 by week
16, although the majority of that change (a 13.6-point drop)
occurred in the first 3 weeks (Anonymous, 2014).
In treatment-resistant unipolar major depression, there
is one negative phase II study of 231 patients (both at a
very low dose 0.1–0.3 mg/day and low dose 1.0–2.0 mg/day;
Forest Laboratories, Inc., 2011), and one positive study of 819
patients (only high dose, 2.0–4.5 mg/day + antidepressant,
separated from placebo + antidepressant, p = .0114; Forest
Laboratories, Inc., 2014b).
Cariprazine Safety and Tolerability
In a systematic review of the literature, a total of 12 articles
were found that described the safety and tolerability of
cariprazine in humans: seven were review articles (Caccia,
Invernizzi, Nobili, & Pasina, 2013; Citrome, 2013a, 2013b,
2013c; El-Mallakh, Elmaadawi, Gao, Lohano, & Roberts,
2011; George, Amrutheshwar, Rajkumar, Kattimani, &
Dkhar, 2013; Javitt, 2015), four were short-term (6-week),
double-blind, randomized controlled trials of fixed-dose
cariprazine used in the acute treatment of schizophrenia
with results reported in poster sessions or industry press
releases, and one was a 3-week double-blind, randomized
control trial of cariprazine in mania (Durgam, Nasrallah,
et al., 2014; Durgam et al., 2015; Forest Laboratories,
Inc., 2012b; Lieberman et al., 2013; Zukin et al., 2012).
Cariprazine was found to significantly reduce symptoms of
schizophrenia in lower oral dose ranges (1.5 mg once daily)
and treatment effects were greater in doses of 3.0–4.5 mg
once daily, but tolerability was not dose related (Durgam,
Starace, et al., 2014). Significantly more placebo-treated
subjects discontinued treatment (21.9%) compared with
cariprazine- (10.2–12.4%) or risperidone-treated (9.3%)
due to insufficient therapeutic response (Durgam, Starace,
et al., 2014). When treatment-emergent side effects were
compared with other FDA-approved second-generation
atypical antipsychotics such as risperidone, olanzapine,
ziprasidone, paliperidone, iloperidone, asenapine, and
lurasidone, cariprazine was considered to be less likely to
produce clinically significant metabolic side effects such
as weight gain, hyperlipidemia, hypercholesterolemia, and
hyperglycemia, and was not associated with significant ECG
(electrocardiogram) abnormalities or increased prolactin
levels (Citrome, 2013a). In one randomized controlled-
trial of the safety and efficacy of cariprazine compared with
risperidone in people with acute symptoms of schizophrenia,
when increases in metabolic parameters occurred, they were
small and similar to placebo (Durgam, Starace, et al., 2014).
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Table 3. Adverse Events in Bipolar Patients in the Only Published Study occurred in 9–15% of cariprazine-treated subjects, compared
(37) with 5–9% of placebo-treated subjects.
AE Cariprazine (n = Placebo (n = In longer-term trials with subjects with bipolar illness (a
118, n [%]) 118, n [%]) 16-week open study), akathisia was the most common AE,
occurring in 37% of patients; parkinsonism was the second
Discontinuation due to 17 (14.4) 12 (10.2) most common AE, occurring in 7% of patients. But only 5%
AE
dropped out of the study due to AEs (Anonymous, 2014).
Parkinsonism 29 (24.6) 11 (9.3)
Headache 23 (19.5) 24 (20.3)
In sum, cariprazine was considered safe and well tolerated
Akathisia 22 (18.6) 7 (5.9) among adult patients diagnosed with acute schizophrenia.
Nausea 18 (15.3) 12 (10.2) Phase II clinical trials of the safety and tolerability of
Constipation 18 (15.3) 10 (8.5) cariprazine in the treatment of bipolar disorder and
Dyspepsia 15 (12.7) 8 (6.8) as adjunctive treatment with antidepressants for major
Dizziness 11 (9.3) 8 (6.8) depressive disorder are underway; therefore, these data are
Vomiting 10 (8.5) 4 (3.4)
not yet available (El-Mallakh et al., 2011; George et al., 2013).
Insomnia 10 (8.5) 3 (2.5)
Diarrhea 7 (5.9) 8 (6.8)
Restlessness 7 (5.9) 1 (0.8) Conclusions
Sedation 7 (5.9) 1 (0.8)
Blurred vision 7 (5.9) 1 (0.8) Cariprazine is a partial agonist antipsychotic with greater
Others not different: 3–5 (2.5–5.1) 3–8 (2.5–6.8) affinity to the D3 receptor. This receptor appears to be
mania, pain in extremity, involved in aspects of motivation and cognition. However,
pyrexia, tremor,
the clinical development program has focused on disorders
agitation, and toothache
Total 101 (85.6) 93 (78.8)
and the approval process. Consequently, the strengths of this
medication may not be evident in the pivotal registrational
trials needed for regulatory approval. In studies with patients
with bipolar mania, cariprazine has shown significant efficacy
Although no clear relationship between dosages was seen, and a tolerable adverse effect profile. The studies examining
Durgam, Starace, et al. (2014) reported that the most frequent its efficacy in bipolar depression have been inconsistent, but
cariprazine treatment-emergent side effects (ࣙ5% and two the data are consistent with the interpretation of a window
times the placebo rate) were insomnia, extrapyramidal in which the drug may be effective for depression, in a
symptoms, akathisia, sedation, nausea, and constipation; manner similar to aripiprazole and brexpiprazole. Given the
Citrome (2013a) reported a similar side effect profile but limited resources of the companies introducing this drug, it
included the additional side effects of dizziness, vomiting, is unlikely that further development of the indications for
and anxiety. depression will take place in the near future. The true benefit
In 118 patients with bipolar illness receiving an average of this drug still needs to be revealed in secondary analyses
of 8.8 mg/day for 3 weeks and 112 receiving placebo, 75 of negative symptoms, cognition, and motivation in patients
(63.6%) and 73 (61.9%) completed the study, respectively with schizophrenia and bipolar illness.
(Durgam et al., 2015). Adverse events (AEs) were common
in both groups (Table 3), with extrapyramidal symptoms,
Implications for Nursing Practice
akathisia, and various gastrointestinal symptoms being the
most predominant. When akathisia is measured (utilizing Partial agonists of the dopamine system are the preferred
the Barnes Akathisia Rating Scale), there is no significant class of medications over pure antagonists in treatment
increase in akathisia with cariprazine (0.4 vs. 0.09 for placebo, of both psychosis and mood disturbance. This is because
p = .12; Durgam et al., 2015). Parkinsonism, as measured tolerance to the medication is less likely to occur when
by the Simpson Angus Scale, was significantly greater in the receptor is both blocked and stimulated at the same
patients receiving cariprazine (1.17, placebo 0.09, p < .01). time. Including cariprazine, there are now three available
When examined as a threshold phenomenon, 19 (16.1%) antipsychotic medications with partial agonist effects,
cariprazine-treated patients experienced an SAS score >3 but development of alternatives is still an unmet need.
(at any post-baseline assessment), and one (0.09%) placebo- Cariprazine is a partial agonist at both D2 and D3 receptors.
treated patient had such a score (z = 1.65, not significant). The affinity at the D3 receptor is some six times greater
In the unpublished phase III mania trials reported by than at the D2 receptor. However, since the drug must still
Citrome (2013b), AEs were greater with higher doses (6– occupy over 65% of the D2 receptor to exhibit antipsychotic
12 mg/day) compared with lower doses (3–6 mg/day), and (and presumably antimanic) efficacy, the huge difference in
both greater than placebo. Motor and gastrointestinal AEs affinity is not as significant as it might seem.

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Cariprazine for the Treatment of Bipolar Disorder
Studies with partial agonists, particularly with long half-
lives, are frequently difficult to predict, and this appears to
be the case with cariprazine. It is easy to interpret the acute
mania studies, but it is much more difficult to interpret
the bipolar depression data. The task of understanding the
effect of the drug is made more difficult by the paucity of
publications of the completed clinical trials. Additionally,
given the limited resources of the relatively small companies
that are developing cariprazine, and the initial difficulties
with FDA approval, it is unlikely that additional development
of the bipolar depression indications will be undertaken.
Prescribing nurses can use cariprazine if they believe
that the antipsychotic medication will be used for long
periods of time, because the partial agonist effects will
reduce the likelihood of tachyphylaxis (acclimation to
the medication). Cariprazine may be better than other
antipsychotics regarding metabolic adverse consequences,
but has significant association with akathisia, extrapyramidal
symptoms, and gastrointestinal consequences. Most side
effects begin at a fairly low dose. In general, using the lowest
dose will not significantly reduce side effects since efficacy is
dose related, but side effects are not dose related.
It is important to remember that pharmacotherapy must
be combined with other forms of treatment. Education,
support, and other forms of psychotherapeutic interventions
are required to optimize outcome. Empowering psychiatric
patients is a potent tool. Having the patient involved in
determining the optimal dose is usually a helpful approach.
This requires ceding some control to the patient in dose
finding, and a drug such as cariprazine that has dose-related
efficacy but not dose-related AEs is ideal for this.
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