Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: https://www.tandfonline.com/loi/iern20

Cariprazine for the treatment of bipolar

depression: a review

Renee-Marie Ragguett & Roger S. McIntyre

To cite this article: Renee-Marie Ragguett & Roger S. McIntyre (2019): Cariprazine for
the treatment of bipolar depression: a review, Expert Review of Neurotherapeutics, DOI:
10.1080/14737175.2019.1580571

To link to this article: https://doi.org/10.1080/14737175.2019.1580571

Accepted author version posted online: 12

Feb 2019.

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Publisher: Taylor & Francis

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2019.1580571

Drug profile

Cariprazine for the treatment of bipolar depression: a review

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Renee-Marie Ragguett1, Roger S. McIntyre1,2,3*

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1
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada
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Department of Psychiatry, University of Toronto, Toronto, Canada

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3
Department of Pharmacology, University of Toronto, Toronto, Canada

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*Corresponding author: Roger S. McIntyre, Departments of Psychiatry and Pharmacology, University of
Toronto, Toronto, Ontario, Canada; Mood Disorders Psychopharmacology Unit, University Health
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Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8; Email: roger.mcintyre@uhn.ca
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Abstract

Introduction: Depressive symptoms and episodes dominate the course of bipolar disorder. The

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morbidity of bipolar disorder is disproportionately mediated by depressive symptoms; economic costs of

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bipolar disorder are also disproportionately due to unremitting depressive symptoms. Relatively few
treatment options have established unequivocal efficacy in the treatment of bipolar depression. Herein
we review evidence regarding the efficacy of the D3 preferring D2/D3 partial agonist cariprazine in the

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treatment of adults with bipolar depression.
Areas covered: Randomized controlled trials that sought to determine the efficacy, tolerability, and
safety of cariprazine in adults with bipolar I depression.

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Expert opinion: The available evidence from clinical trials indicates that cariprazine is effective at
treating bipolar depression wherein treatment for bipolar depression remains an unmet need in bipolar
disorder. Cariprazine has demonstrated good tolerability and safety profiles in bipolar disorder.
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Furthermore, cariprazine may be effective in improving both anhedonia and cognitive dysfunction. Long
term prevention studies in bipolar depression, as well as separate studies evaluating efficacy in adults
with bipolar II depression, are needed.
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Keywords: Bipolar depression, bipolar disorder, cariprazine, D2/D3 partial agonist, pharmacotherapy
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1.0 Introduction

Bipolar disorder (BD) is a chronic and debilitating illness which can be characterized by episodes

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of mania and depression. In many BD subtypes, episodes of depressions are longer in duration than

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those of mania, thus patients are spending a longer time in depressive episodes [1]. Depressive episodes
are a significant target for treatment given that depression is the leading cause of disability worldwide
and has a significant negative impact on workplace productivity [2, 3]. Additionally, those with BD report

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depressive symptoms as being more disruptive to social and occupational functioning in comparison to
manic symptoms [4]. Remission rates for bipolar depression are between 30% and 60% following
adequate treatment [5]. Despite the severity of impairments and low remission rates associated with

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bipolar depression, there remains a paucity in treatment options.

Atypical (second generation) antipsychotics such as quetiapine are commonly used as a first line
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treatment in bipolar depression. Antidepressant effects from atypical antipsychotics are observed from
serotonin-mediated effects, norepinephrine-mediated effects and dopamine-mediated effects [6]. Each
of the aforementioned systems have been typically implicated in antidepressant mechanisms of action
by the monoamine hypothesis which predicts depressive pathophysiology to be associated with
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decreased levels of serotonin, norepinephrine, and/or dopamine. The dopaminergic system has been of
particular interest in bipolar depression, however there are inconsistencies in the literature surrounding
dopamine release and post-synaptic dopamine receptor density in those with bipolar depression
compared to healthy controls [7].
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Antipsychotics are often classified by their relative actions across dopamine receptors. For
example, second generation antipsychotics act via dopamine D2 and serotonin 5-HT2A antagonism. Of
note, second generation antipsychotics have been associated with problematic weight gain [8, 9].
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Though the mechanism underlying the weight gain is unknown, it has been suggested to be a multitude
of factors including the genetic profile of the patient and interactions of various receptors (e.g.,
serotonergic, dopaminergic, and histaminergic) [10]. Recently, third generation antipsychotics (e.g.,
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aripiprazole) have entered the market with a unique mechanism of action, partial agonism of the D2
receptor, these novel antipsychotics may prove to have an improved therapeutic profile for BD over
their second generation counterparts offering the same benefits and an improved metabolic profile [11].
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Cariprazine is a novel therapeutic acting as a partial D2, D3 receptor agonist with preference for
the D3 receptor, whereas many other antipsychotics prefer the D2 receptor. Notably, the dopamine D3
receptor has been suggested as a target for the treatment of unipolar depression [12]. Pre-clinical
studies have demonstrated that administration of a selective D3 receptor antagonist significantly
increase the concentration of dopamine, norepinephrine, and acetylcholine in the anterior cingulate
cortex (ACC) without an increase in serotonin [13]. Indeed, dysregulation of the ACC has been implicated
in the pathophysiology of the various mood states observed in BD [14]. Cariprazine has demonstrated in
pre-clinical studies to have antidepressant, antianhedonic, antipsychotic, and pro-cognitive effects [15,
16]. The foregoing observations provide the basis for hypothesizing that cariprazine may be effective in
adults with bipolar depression.

1.1 Overview of the market

Though atypical antipsychotics are commonly used to treat BD, the episode type determines
treatment regimen wherein acute depressive episodes and acute manic episodes are treated differently.
For example, first line treatment for a depressive episode would be quetiapine or lurasidone
monotherapy, alternatively lurasidone adjunctive to lithium or divalproex. In contrast, first line

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treatment for a mild to moderate manic episode would be lithium monotherapy, or monotherapy with

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aripiprazole, asenapine, divalproex, quetiapine, risperidone or ziprasidone [17].

Despite the availability of treatments for bipolar depression, the majority of experiences in

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morbidity associated with BD is with a depressive episode. This suggests both more effective treatments
for manic episodes and a paucity of effective treatments for depressive episodes [18]. Moreover,
quetiapine is limited by sedation/somnolence, as well as propensity for weight gain/metabolic

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disturbance [19]. Lurasidone has been recently approved to treat bipolar depression and while it has
demonstrated efficacy in treating mood symptomatology, lurasidone has also been associated with
extrapyramidal symptoms [20, 21].
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Cariprazine is a unique D3 preferring partial D2, D3 receptor agonist. Although aripiprazole and
brexpiprazole exert partial agonism at the D2/D3 receptors, the relative selectivity of cariprazine (at
lower doses) for D3 relative to D2 is relatively greater than both aripiprazole and brexpiprazole [22].
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Moreover, the pharmacologically active metabolites of cariprazine dimethyl-cariprazine (DCAR) and
didesmethylcariprazine (DDCAR) have a relatively greater affinity for the D3 receptor relative to the D2
receptor. Additionally, cariprazine and aripiprazole are indicated only for the treatment of bipolar
mania. Randomized controlled trials with aripiprazole in acute bipolar depression, failed to identify
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significant advantages in favour of aripiprazole relative to placebo [23]. Hitherto no large randomized
controlled trials have been conducted with brexpiprazole in acute bipolar depression.

2.0 Introduction to the drug

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Cariprazine is an oral antipsychotic co-developed by Gedeon Richter Plc is now licenced to Allergan
in North America, and undergoing development in Japan by Mitsubishi-Tanabe Pharma Corporation
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[24].

2.1 Chemistry
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Cariprazine (IUPAC name: 3-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-1,1-

dimethylurea) is a D3 preferring partial D2, D3 receptor agonist and has the molecular formula
C21H32Cl2N4O with a molecular weight of 427.41 g/mol. The chemical structure of cariprazine is seen in
Figure 1.

2.2 Pharmacodynamics

In vitro binding profiles of cariprazine have shown a preferential selectivity for D3 receptors versus
the D2 receptors. Picomolar affinity was observed for D3 receptors and subnanomolar affinity for the D2L
and D2S subtypes of the D2 receptors and the 5-HT2B receptor wherein the D3 receptor had the higher
affinity. Additionally, nanomolar affinity was observed for the 5-HT1A receptor and moderate activity was
observed for 5-HT2A, H1 and σ1 receptors (Table 1). Other receptors demonstrating a lower affinity (i.e., a
pKi < 7) include the 5-HT2C, 5-HT6, 5-HT7, α1D-AR, α2A-AR, and β-AR [25].

Cariprazine functioned as a potent partial agonist with an Emax of 70.9% as observed by in vitro
functional activity at the D3 receptor, partial antagonistic activity was also observed at the D3 receptor
with an AAmax of 27%. Similar behaviour was observed at the D2 receptor wherein cariprazine functioned
as a partial agonist with an Emax of 30% and a partial antagonist with an AAmax of 81%. Additionally,

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partial agonism was observed at the 5-HT1A receptor and weak antagonist activity was observed at the 5-

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HT2A receptor [25]. There are however conflicting reports on cariprazine activity, as at the 5-HT1A
receptor cariprazine acted as a full agonist. This difference has been suggested to depend on the assay
system used or, dependant on receptor reserve wherein a partial agonist can behave like a full agonist

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with high levels of receptor reserve [26, 27].

In rodent models, long-term effects of cariprazine included changes in forebrain receptors including

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increased D2 receptor levels in the medial prefrontal cortex, nucleus accumbens, medial and lateral
caudate putamen and hippocampus. As well as increased D3 receptor levels in the islands of Calleja,
olfactory tubercles and nucleus accumbens shell. Additionally, increased 5-HT1A receptors in
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hippocampal CA1 and CA3 regions, A-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA)
receptors in the hippocampal CA2, and CA3 regions, and 5-HT1A receptors in the middle prefrontal cortex
and dorsolateral prefrontal cortex. Reduced N-methyl-D-aspartate (NMDA) receptor binding in the
nucleus accumbens, medial and lateral caudate putamen and hippocampal CA1[28].
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An open-label study examined the striatal dopamine D2 and D3 receptor occupancy in healthy
subjects following one or multiple dosing of cariprazine. It was observed that multiple dosages of
cariprazine resulted in occupancy of greater than 70% of D2 and D3 receptors as measured by positron
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emission tomography [29].

2.3 Pharmacokinetics and metabolism

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The pharmacokinetic profile of cariprazine has been characterized using single and multiple doses of
oral cariprazine in healthy male subjects wherein single doses ranged from 0.5mg to 2.5mg, and multiple
doses ranged from 0.5mg every other day to 1.0mg daily. Following a single dose under fasting
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conditions, maximum plasma concentration was achieved within 3 - 4 hours. Non-fasting conditions
resulted in a delay of maximum plasma concentration, however it did not impact the extent of
absorption. The terminal deposition half-life was reported at 5 - 6 days. Following a single dose of
cariprazine, plasma concentration time curves showed dose-proportionality of exposure of area under
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the curve (AUC). Additionally, with multiple doses, there was an accumulation of both cariprazine and its
metabolites –)DCAR and DDCAR– wherein steady state plasma concentrations were achieved within one
week. Exposure to the metabolite DCAR was 20 to 30% of exposure to cariprazine. Elimination rate was
prolonged with DDCAR with a terminal half life of 2 – 3 weeks [30]. In vitro studies have demonstrated
that cariprazine is metabolised by hydroxylation and demethylation, and specifically metabolized by
CYP3A4 and to a lesser extent by CYP2D6. Cariprazine was found to be excreted in the urine (~21% of
the daily dose) wherein 1.2% of the daily dose was excreted as unchanged cariprazine [31].

3.0 Clinical efficacy

Clinical trials are summarized in in Table 2, and detailed summaries where available were summarized
below.

3.1 Literature search methodology

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Clinical trials were identified by searching online databases www.clinicaltrials.gov and

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www.clinicaltrialsregister.eu using keywords “cariprazine”, “RGH-188”, “bipolar depression”, and
“bipolar disorder”. Additionally, the condition/medical condition header was searched for bipolar
depression. Identified clinical trials were cross referenced using their trial identifier numbers in online

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databases PubMed and Google Scholar for peer reviewed, published results. Finally, the sponsor’s press
releases were searched using keyword “cariprazine” for non-peer reviewed trial results.

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3.2 Clinical evidence

NCT01396447 [32]. Participants were randomized to either placebo or treatment, wherein treatment
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was 0.75 mg/day, 1.5 mg/day, or 3.0 mg/day of oral cariprazine. Least squares mean differences (LSMD)
was used to assess the change from baseline to week 6 in the Montgomery-Åsberg Depression Rating
Scale (MADRS) score. There were significant improvements observed for the treatment group when
compared to placebo specifically for cariprazine 1.5 mg/day (LSMD = -4.0, adjusted p = 0.003). When
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assessed using an ANCOVA with last observation carried forward, all doses of cariprazine produced
significant improvements on the MADRS (0.75 mg/day LSMD = -2.3, p = 0.0041, 1.5 mg/day LSMD = -4.1,
p < 0.001, 3.0 mg/day LSMD = -2.7, p = 0.017). Furthermore 1.5 mg/day cariprazine produced a
significant difference when compared to placebo on the Clinical Global Impressions-Severity (CGI-S)
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scale (LSMD -0.4, adjusted p = 0.013) and when assessed using an ANCOVA with the last observation
carried forward, cariprazine of 1.5 mg/day and 3.0 mg/day produced a significant different from placebo
(LSMD = -0.4 p = 0.001, LSMD = -0.3, p = 0.024 respectively). There were two cases of serious adverse
events considered related to treatment – depression and hypomania. Furthermore, of all participants
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receiving cariprazine, those in the 3.0 mg/day group had the highest frequency of participants
discontinuing due to adverse events. The greatest number of adverse events were minor wherein those
with the highest reported frequency were nausea, insomnia, headache, and akathisia. Notably, 94% of
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the cases of akathisia were mild to moderate and did not result in discontinuation of the study. Changes
in vital signs were small and similar across groups; however, a significant increase in body weight was
observed in a small percentage of the treatment group (2% of the .75 mg/day group; 7% of the 1.5
mg/day group; 5% of the 3.0 mg/day group).Overall, the authors suggested better cariprazine
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tolerability with 1.5 mg/day given their results.

NCT00852202 [33]. In a second study, cariprazine was evaluated in bipolar depression by assigning
participants to one of 3 experimental groups – 0.25 mg/day - 0.75 mg/day, 1.5 mg/day - 3.0 mg/day, or
placebo. The primary outcome measure of change from baseline to 8 weeks on the MADRS was not
significant for either group compared to placebo (group 0.25 mg/day – 0.75 mg/day, p = 0.7408 and
group 1.5 mg/day – 3.0 mg/day, p = 0.9961). The secondary outcome measure of change in Clinical
Global Impressions – Improvements (CGI-I) scale from baseline to week 8 was also not significant for any
group compared to placebo (group 0.25 mg/day – 0.75 mg/day, p = 0.3441 and group 1.5 mg/day – 3.0
mg/day, p = 0.2683). The majority of adverse events reported were minor, with the most frequently
reported events being nausea, diarrhea, akathisia, headache, and insomnia. Weight increases were also
reported in 1% of the 0.25 mg/day – 0.75 mg/day group and 8% of the 1.5 mg/day - 3.0 mg/day group
however the extent of the weight increase was not reported.

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3.3 Phase III trials

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NCT02670551, NCT02670538 [34]. Allergan has briefly provided results from two studies through a press
release. In these studies, participants were assigned to one of three experimental groups – cariprazine

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1.5 mg/day, 3.0 mg/day, or placebo. It was observed that cariprazine significantly improved MADRS
scores from baseline to 6 weeks, demonstrating reduction in depressive symptoms (no significance
value available). It was also suggested that cariprazine was well tolerated and the most frequently

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reported adverse events were nausea, akathisia, restlessness and upper respiratory tract infection. The
results of this study along with the foregoing two studies, indicate that cariprazine exhibits replicated
evidence of efficacy in bipolar depression.
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4.0 Safety and tolerability

Cariprazine was well tolerated in the clinical trials wherein the most common adverse events were
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nausea, diarrhea, akathisia, restlessness, and insomnia [33]. Adverse events resulting in discontinuation
from the study were akathisia, agitation and anxiety. Serious adverse events found related to cariprazine
in one trial were depression and hypomania observed in one patient each. Changes in laboratory values
were small and similar across all groups, however slight weight gain was seen in all cariprazine groups.
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Extrapyramidal side effects occurred infrequently [32]. The side effects profile of cariprazine can also be
compared across treatment indications. De Berardis et al. (2016) provided a summary of clinical trials
that used cariprazine in schizophrenia, bipolar disorder, and major depressive disorder and the authors
concluded across these indications that cariprazine had a good side effects profile and may be
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considered safe. Of their summarized clinical trials, regardless of indication, common adverse events
included nausea, diarrhea, insomnia, and akathisia. Additionally, there were limited occurrences of
extrapyramidal side effects observed in both bipolar disorder and schizophrenia and overall limited
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reports of significant changes in metabolic parameters [35].

5.0 Regulatory affairs

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Cariprazine is approved by the U.S Food and Drug Administration for treatment of manic and mixed
episodes associated with bipolar disorder, as well as the acute and maintenance treatment of
schizophrenia (initial approval in 2015). The European Commission has currently approved the use of
cariprazine for the treatment of schizophrenia (approval in 2017). Japan’s Mitsubishi-Tanabe Pharma
Corporation (MTPC) is developing cariprazine for use in schizophrenia and are currently in phase 2b/3
trials [24]. Additional therapeutic targets that are being studied with cariprazine include but are not
limited to, negative symptoms in schizophrenia, as well as adjunctive treatment in adults with MDD
experiencing an inadequate response to conventional anti-depressants [34]. De Berardis et al (2016)
have conducted a review of clinical trials using cariprazine with various indications including
schizophrenia, bipolar disorder, and major depressive disorder [35]. In September 2018, the FDA
released a statement indicating that it has accepted for review a supplemental New Drug Application for
cariprazine for treatment of bipolar depression in adults with an expected decision in Q1-Q2 2019 [34].

6.0 Conclusion

Cariprazine offers a novel mechanism for treating bipolar depression by having a preferential
selectivity for dopamine D3 receptors versus the dopamine D2 receptors. The majority of the trials with
results available demonstrate efficacy compared to placebo on the MADRS [32, 33, 34]. Cariprazine was

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also well tolerated, with minor adverse events. Indeed, the present review was completed on the basis

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of limited available evidence at the time of writing and represents the available results. Additional
studies with longer durations are needed to assess weight gain during treatment in order to determine if
cariprazine is subject to the same metabolic profiles as other antipsychotics as the available evidence

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suggests that there is potential for cariprazine to be associated with problematic weight gain similar to
second generation antipsychotics. Furthermore, while akathisia appears to be a recurrent adverse
event, extrapyramidal symptoms overall do not appear often, and akathisia was generally classified as

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mild or moderate [32]. Regardless, additional long-term studies assessing the occurrences and extent of
akathisia would be beneficial in further classifying the safety profile of cariprazine.
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7.0 Expert opinion

Notwithstanding the development and in many cases, regulatory approval of mechanistically

distinct agents across various phases of bipolar disorder, bipolar depression remains one of the most
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significant unmet needs in bipolar disorder. Available evidence indicates that cariprazine is highly
effective, well tolerated, and safe in the treatment of bipolar depression, at both 1.5 and 3.0 mg per
day. The D3 preferring pharmacodynamic profile of cariprazine (at lower doses i.e. 1.5 mg or less)
provides the basis for hypothesizing that in addition to reducing total depressive symptoms, cariprazine
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may also be effective in improving measures of anhedonia, as well as cognitive dysfunction. Specifically,
pre-clinical models have informed both the use of a low dose as efficacy was observed at these doses,
and suggest improvements in anhedonia and cognition [36, 37]. Long term prevention studies in bipolar
depression, as well as separate studies evaluating efficacy in adults with bipolar II depression, are
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warranted. It is a testable hypothesis that cariprazine’s efficacy in reward and cognitive subdomains may
improve treatment acceptability and overall patient reported outcomes in bipolar disorder.
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During the next 5 years, the study of cariprazine in bipolar II depression, as well as in the recurrence
prevention of bipolar depression is warranted. The pharmacodynamic profile of cariprazine and pre-
clinical results provide the basis that it may be capable of offering at improvement in measures of
anhedonia as well as cognition [36, 37, 38]. Recent product insert updates for vortioxetine include
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mention that it is capable of improving cognitive function in adults with major depressive disorder. No
existing agent FDA approved for bipolar depression has language approved by the FDA indicating anti-
anhedonia and/or pro-cognitive effects independent of improvement on total depressive symptoms.
Evidence supporting such a product insert update would be of enormous significance to the field.
Furthermore, the evaluation of cariprazine’s efficacy in bipolar disorder in individuals with comorbid
alcohol and/or substance use disorders, would be justified in light of cariprazine’s pharmacodynamic
profile. The high prevalence of, and hazards posed by alcohol and substance use disorders are
enormous, and currently there is no treatment for bipolar disorder that is particularly robust in
mitigating substance use behaviour. The evidence for cariprazine as an adjunct in major depressive
disorder, will be instructive. Combining cariprazine with “rapid onset” treatments for mood disorders
e.g. ketamine, rapastinel, would be very interesting particularly in bipolar depression. Furthermore,
second generation antipsychotics have been examined for treatment of acute BD with mixed features
and results have been summarized by a meta-analysis [39]. While this meta-analysis is rather
preliminary, improvements in the MADRS and Young Mania Rating Scale (YMRS) were observed. Indeed,
clinical trials exploring the use of cariprazine for treatment of BD with mixed features would be of
interest, at time of writing, there is one clinical trial studying the prevention of relapse in BD with
current manic or depressive episode, with or without mixed features (NCT03573297).

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Funding

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This paper was not funded
Declaration of Interest

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RS McIntyre has the following disclosures: During the past two years, RS McIntyre has received fees for
speaking/consultation from the following pharmaceutical companies: Shire, Purdue, Otsuka, Janssen-
Ortho, Lundbeck, Pfizer, Neurocrine, Neuralstem, Sunovion, Takeda, Allergan. During the past two years,

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RS McIntyre has received research support from: Lundbeck, Shire, Purdue, Allergan. RS McIntyre has
also received research grants from Stanley Medical Research Institute. The authors have no other
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
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employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents
received or pending, or royalties.

Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other relationships to disclose
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Table and figure legends
Figure 1: Structure of cariprazine

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Table 1: Cariprazine binding affinity by receptor

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Receptor pKi
D3 10.07
D2S 9.16
D2L 9.31
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5-HT1A 8.59
5-HT2A 7.73
H1 7.63
σ1 7.74
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Table 1: Cariprazine binding affinity by receptor
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Table 2: Clinical trial summaries

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Study Study on the Study of the A Cariprazine Study in Safety, Safety and
Title Efficacy, Efficacy of a the Prevention of Tolerability, Efficacy of
Safety, and Fixed-dose Relapse in Bipolar I and Efficacy RGH-188
Tolerability of Regimen of Disorder Patients of Cariprazine (Cariprazine) in
Cariprazine Cariprazine Whose Current Episode in Bipolar
Relative to Compared to is Manic or Depressive, Participants Depression
Placebo in Placebo for With or Without Mixed With Bipolar
Patients With Treatment of Features Depression
Bipolar I the

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Depression Depressive

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Episode in
Patients With
Bipolar I

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Disorder
Official A Phase 3, A Phase 3, Double-blind, Placebo- A Double- A Double-blind,
Title Randomized, Randomized, controlled, Randomized Blind, Placebo-

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Double-Blind, Double-Blind, Withdrawal, Placebo- controlled
Placebo- Placebo- Multicenter Clinical Trial Controlled Study of RGH-
Controlled, Controlled, Evaluating the Efficacy, Evaluation of 188
Parallel- Parallel-
an
Safety and Tolerability the Safety (Cariprazine) in
Group, Group, of Cariprazine in a Dose- and Efficacy Bipolar
Multicenter, Multicenter, reduction Paradigm in of Cariprazine Depression
Fixed-Dose Fixed-Dose the Prevention of in Patients
M
Clinical Trial Clinical Trial Relapse in Bipolar I With Bipolar
Evaluating Evaluating Disorder Patients Depression
The Efficacy, The Efficacy, Whose Current Episode
Safety And Safety And is Manic or Depressive,
ed

Tolerability Tolerability With or Without Mixed

Of Of Features
Cariprazine In Cariprazine In
Patients With Patients With
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Bipolar I Bipolar I
Depression Depression
Trial NCT0267055 NCT0267053 NCT03573297 NCT0139644 NCT00852202
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Identifier 1 8 7
Study Completed Completed Recruiting Completed Completed
Status
Phase 3 3 3 2 2
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Type of Randomized, Randomized, Randomized, parallel Randomized, Randomized,

Study parallel parallel assignment, double parallel parallel
assignment, assignment, masked (participant, assignment, assignment,
quadruple quadruple investigator) quadruple double masked
masked masked masked (participant,
(participant, (participant, (participant, investigator)
care care care
provider, provider, provider,
investigator, investigator, investigator,
 and and outcomes
outcomes outcomes assessor)
assessor) assessor)

Study 6 weeks 6 weeks 52 weeks 8 weeks 8 weeks

Duration
Drug Cariprazine Cariprazine Cariprazine and placebo Cariprazine Cariprazine and
and placebo and placebo and placebo placebo

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Dose Daily -- 1.5 Daily -- 1.5 Daily -- 1.5 mg, 3.0 mg Daily -- .75 Daily -- .25 mg -

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mg, 3.0 mg mg, 3.0 mg mg, 1.5 mg, .75 mg, 1.5 mg
3.0 mg - 3.0 mg

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Primary Change from Change from Number of days to first Change from Change from
Outcome baseline baseline relapse of a mood baseline baseline
Measures MADRS MADRS episode during MADRS MADRS

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treatment period (12 (Baseline to (Baseline to
weeks to 52 weeks) Week 6) Week 8)
Secondar Change from Change from N/A Change from Change from
y baseline in baseline in baseline in baseline in CGI-
Outcome CGI-S CGI-S
an CGI-S I (Baseline to
Measures (Baseline to Week 8)
Week 6)
N Actual 488 Actual 493 Estimated 822 Actual 584 Actual 234
M
Published No. Limited No. Limited No Yes [32] No. Limited
results results results
available available available on
from sponsor from sponsor clinicaltrials.go
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[34] [34] v [33]

Table 2: Clinical trial summaries

MADRS: Montgomery-Åsberg Depression Rating Scale (MADRS)

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CGI-S: Clinical Global Impressions-Severity (CGI-S)

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