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Cariprazine for Treating Schizophrenia, Mania,
Bipolar Depression, and Unipolar Depression: A
Review of Its Efficacy
Martin Tarzian , Mariana Ndrio , Srujan Kaja , Elisabeth Beason , Adegbenro O. Fakoya
1. Psychiatry, University of Medicine and Health Sciences, Basseterre, KNA 2. Psychiatry and Behavioral Sciences,
University of Medicine and Health Sciences, Basseterre, KNA 3. Psychiatry, Larkin Community Hospital, Miami, USA 4.
Cardiology, University of Medicine and Health Sciences, Basseterre, KNA 5. Cellular Biology and Anatomy, Louisiana
State University Health Sciences Center, Shreveport, USA
Corresponding author: Adegbenro O. Fakoya, gbenrofakoya@gmail.com
Abstract
This drug review presents a comprehensive review of Cariprazine, a medication that received FDA approval
in 2015 for treating schizophrenia and bipolar disorder. The paper begins by exploring Cariprazine's
mechanism of action, which involves modulating dopamine and serotonin receptors. Additionally, the
review assesses Cariprazine's metabolic profile and notes its low potential for weight gain and metabolic
side effects. The study examines Cariprazine's efficacy and safety in treating various psychiatric disorders,
such as schizophrenia, bipolar maintenance, mania, and bipolar depression. A meticulous analysis of
clinical trials is included, demonstrating Cariprazine's potential advantages over existing medications used
for these disorders. Additionally, the review covers Cariprazine's recent approval as an adjuvant treatment
for unipolar depression. Furthermore, the paper examines the limitations of Cariprazine, such as the absence
of head-to-head trials comparing it to other commonly used medications for these disorders. The paper
concludes by emphasizing the need for more research to establish Cariprazine's position in treating
schizophrenia and bipolar disorder and determine its comparative effectiveness with other available
treatments.
Categories: Family/General Practice, Psychiatry, Therapeutics
Keywords: psychiatric disorders, bipolar depression, unipolar depression, major depression, schizophrenia,
cariprazine
Introduction And Background
Psychotic disorders such as schizophrenia and mood disorders such as major depression and bipolar disorder
are complex and multifaceted mental illnesses that can severely impair an individual's daily functioning and
quality of life [1,2]. According to the Institute of Health Metrics and Evaluation's latest data, in 2019,
approximately 280 million individuals worldwide lived with depression, including 23 million children and
adolescents, while 40 million people lived with bipolar depression [3-5]. Although schizophrenia is not as
prevalent as other psychiatric disorders, affecting around 24 million individuals globally, the World Health
Organization considers it one of the top 10 illnesses that significantly contribute to the global burden of
disease, with devastating outcomes for affected individuals, including financial ruin [3-6].
Previously, managing major depression, bipolar disorders, and schizophrenia required different
pharmacological treatments, with antidepressants, mood stabilizers, and antipsychotics used to address
each disorder [7]. While first-generation antipsychotics were the gold standard for treating schizophrenia, a
shift in treatment paradigm occurred in the late 1990s with the emergence of novel atypical antipsychotic
agents [8]. These newer agents had a more favorable safety and tolerability profile than the first-generation
antipsychotics, attributed to their less specific antagonistic activity at the D2 receptor and relatively
stronger serotonin 5-HT2A receptor action [9]. This mechanism not only reduced the potential for
developing extrapyramidal symptoms (EPS), which was a treatment-limiting side effect of first-generation
antipsychotics, but also allowed these agents to be used in the treatment of a broader range of conditions
other than in schizophrenia, including bipolar disorder and major depression, where they can be used as an
adjunctive therapy or even a monotherapy [9]. A study revealed that atypical antipsychotics were prescribed
to more than 70% of patients with nonpsychotic conditions such as anxiety disorders and bipolar disorder for
mood stabilization [9].
According to data collected from the National Health and Nutrition Examination Survey spanning from 2013
to 2018, approximately 3.8 million adults in the United States, or 1.6% of the population, were found to be
taking antipsychotic medications [10]. Despite their efficacy, significant concerns exist regarding these
agents' side effect profiles, including weight gain, metabolic syndrome, and cardiovascular complications
[8]. At the same time, while at a lesser degree, these agents still possess the potential to predispose to EPS.
As a result, pharmaceutical research has shifted its focus toward identifying newer atypical antipsychotics
that exhibit a more favorable profile regarding adverse effects.
1 2 3 4 5
Open Access Review
Article DOI: 10.7759/cureus.39309
How to cite this article
Tarzian M, Ndrio M, Kaja S, et al. (May 21, 2023) Cariprazine for Treating Schizophrenia, Mania, Bipolar Depression, and Unipolar Depression: A
Review of Its Efficacy. Cureus 15(5): e39309. DOI 10.7759/cureus.39309
Cariprazine (brand name Vraylar) is a more recent addition to a unique group of antipsychotics with a
receptor profile characterized by dopamine D3-preferring D3/D2 receptor partial agonism and serotonin 5-
HT1A partial agonism [11,12]. Studies have shown that cariprazine has a lower risk of causing significant
weight gain, hyperlipidemia, and hyperglycemia [11,12]. Due to this mechanism, cariprazine received FDA
approval in 2015 for treating schizophrenia and acute manic or mixed episodes associated with bipolar I
disorder, and in 2022, it received FDA approval as an adjunctive therapy for treating major depressive
disorder [13].
This pharmacological review provides an in-depth examination of cariprazine, focusing on its mechanism of
action, metabolic profile, clinical effectiveness, and safety in treating various mental illnesses. The article
evaluates the evidence of cariprazine's potential advantages over existing pharmaceuticals and its
limitations, including the absence of head-to-head trials comparing it to other commonly used therapies.
Finally, the study comprehensively overviews cariprazine's role in treating schizophrenia and bipolar
disorder. It highlights areas for further research to determine comparative efficacy and appropriate
therapeutic usage.
Review
Method
For this drug review on Vraylar and its trials, Google Scholar was used to search for relevant research papers,
clinical trials, and other scientific articles related to Vraylar. The search terms included "Vraylar,"
"cariprazine," "clinical trials," "bipolar mania," "bipolar depression," and "schizophrenia." The inclusion
criteria for the articles were that they had to be published in peer-reviewed journals and had to report on the
efficacy and safety of Vraylar in treating schizophrenia or bipolar disorder. The exclusion criteria were
articles that were not related to the topic, duplicate publications, and articles that were not in English. After
a thorough search of the literature, a total of 48 relevant articles were selected for the review. The articles
were read and analyzed for content, and key findings were extracted. The extracted data included the study
design, sample size, inclusion and exclusion criteria, interventions, outcome measures, and results. The
ChatGPT language model (OpenAI, San Francisco, California) was utilized to assist in editing and rewording
the work to ensure coherence and clarity in conveying the findings. In summary, a comprehensive review of
relevant literature on Vraylar was conducted using Google Scholar, and Chat GPT was utilized to assist in
editing. The review included an analysis of the study design, sample size, interventions, outcome measures,
and results of 48 selected articles related to the efficacy and safety of Vraylar in treating schizophrenia and
bipolar disorder.
Mechanism of action
Cariprazine is a unique antipsychotic drug that antagonizes D3 receptors while blocking D2 receptors.
Cariprazine is the only antipsychotic medication targeting dopamine D3 receptors [13,14]. While other
antipsychotic medications may have some affinity for the D3 receptor, they primarily target other dopamine
receptors, such as D2 [14-16].
D3 receptor antagonists have been shown to have potential pro-cognitive effects, including improvements
in attention, working memory, and executive function, in animal models and clinical studies [17,18]. The
clinical significance of cariprazine's unique targeting of D3 receptors is not fully understood; however,
preclinical studies suggest that D3 receptor blockade may have potential therapeutic benefits in treating
schizophrenia and other psychiatric disorders [15].
Cariprazine also has a relatively high affinity for 5HT1A and alpha 1B receptors [11,14,15]. This
pharmacological profile is thought to contribute to its potential efficacy and tolerability in treating
schizophrenia and related disorders. Specifically, high affinity at the 5HT1A receptor is associated with
improved negative symptoms and cognitive deficits [15].
The 5HT1A receptor is a subtype of serotonin receptor widely distributed throughout the brain and involved
in various physiological and psychological processes, including mood, cognition, and stress responses
[19,20]. Activation of the 5HT1A receptor has been shown to have potential antidepressant and anxiolytic
effects and pro-cognitive effects in animal models and clinical studies [19,20]. Cariprazine's high affinity at
the 5HT1A receptor may contribute to its potential efficacy in improving negative symptoms and cognitive
deficits in patients with schizophrenia and bipolar depression [15].
The alpha 1B receptor is a subtype of alpha-adrenergic receptor that is primarily expressed in the central
nervous system and is involved in regulating motor function and cardiovascular activity. Alpha 1B receptor
antagonists have been shown to have antipsychotic effects and reduce EPS [16,20]. Cariprazine's high
affinity at the alpha 1B receptor may contribute to its potential tolerability in treating schizophrenia and
related disorders [11,12,15]. In contrast, high affinity at the alpha 1B receptor is hypothesized to be linked to
reduced EPS, such as parkinsonism and akathisia [16,20].
Metabolic profile and tolerability
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 2 of 16
Unlike many other antipsychotics, studies have demonstrated that cariprazine stands out from other
antipsychotic medications due to its favorable metabolic profile. It carries a lower risk of causing common
metabolic side effects such as significant weight gain, hyperlipidemia, and hyperglycemia [15,21]. Clinical
studies have reported that cariprazine is associated with minimal changes in body weight, BMI, and waist
circumference, even during long-term treatment periods of up to 48 weeks [22-24]. Cariprazine was also
shown to have a lower incidence of metabolic abnormalities such as hyperglycemia and hyperlipidemia
when compared to risperidone [21,23].
The unique pharmacological properties of cariprazine, including its partial agonist activity at the dopamine
D3 receptor and low affinity for the histamine H1 receptor, are thought to contribute to its favorable
metabolic profile [15,21]. Additionally, cariprazine has been shown to have a low risk of causing metabolic
abnormalities such as hyperlipidemia and hyperglycemia. In a study comparing cariprazine to risperidone,
cariprazine was associated with significantly lower increases in fasting glucose and triglyceride levels and a
lower incidence of hyperglycemia and hyperlipidemia [23].
Caccia et al. (2013) performed a thorough review of cariprazine and its side effect profile compared to other
antipsychotics. Cariprazine showed good tolerability in studies involving schizophrenic patients [21]. The
most commonly reported adverse events (AEs) with cariprazine included insomnia, extrapyramidal disorder,
sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation [21]. These side effects, however,
occur at significantly lower rates than in other antipsychotics, such as olanzapine and risperidone [22,23]. In
addition, there were no clinically significant changes observed in metabolic variables, prolactin levels, or
corrected QT (QTc) prolongation (above 500 ms) with cariprazine use. Weight gain was found to be lower
with cariprazine compared to risperidone and placebo [21]. Cariprazine shows minimal changes in blood
pressure, pulse, and body weight observed in cariprazine-treated patients compared to placebo [21]. The
incidence of orthostatic hypotension or ECG changes is similar between cariprazine and placebo groups. No
cariprazine recipients had an ECG QT interval exceeding 500 ms [21].
Cariprazine may cause similar side effects as other second-generation antipsychotics (SGAs) but at a much
lower rate [22,23]. Cariprazine, compared to first-generation antipsychotics and certain SGAs like
olanzapine and risperidone, appears to have a lower prevalence of akathisia, a well-known side effect
associated with antipsychotic treatment [23]. The distress caused by antipsychotic-induced akathisia can be
significant and impact treatment adherence and long-term patient outcomes. However, in clinical practice,
akathisia is routinely managed alongside other diseases or drug-induced symptoms.
In a pooled 48-week dataset, akathisia was the most commonly observed treatment-emergent adverse event
(TEAE) with cariprazine. Most occurrences were reported as mild to moderate in severity and were
considered related to treatment [22]. Akathisia rarely led to treatment discontinuation, with only a small
percentage of patients discontinuing due to this side effect. The onset of akathisia generally occurs within
the first six weeks of treatment [22]. In long-term cariprazine treatment, the majority of patients used
medication to manage akathisia symptoms, regardless of the event's severity. This indicates that most
patients were able to effectively manage akathisia while continuing treatment with cariprazine [22]. Overall,
these findings suggest that cariprazine causes fewer cases of akathisia and that the majority of patients can
effectively manage this side effect while continuing their treatment with cariprazine.
Based on the results of two long-term open-label studies, cariprazine demonstrated a generally safe and
well-tolerated profile. Mean prolactin levels decreased across all dose groups. There were no significant
changes in aminotransferase levels or alkaline phosphatase, and no dose-response relationship was
observed [23]. Metabolic parameters showed insignificant changes, with mean total cholesterol, low-density
lipoprotein, and high-density lipoprotein levels decreasing. There was no clear dose-response relationship
observed for these metabolic parameters. The mean change in body weight was 1.58 kg, with 27% of patients
experiencing weight gain and 11% experiencing weight loss of 7% or more [23].
Cardiovascular parameters, including blood pressure and pulse, did not show clinically significant changes.
The most common EPS-related TEAEs, reported in at least 5% of patients, were akathisia, tremor,
restlessness, and extrapyramidal disorder. In conclusion, these post hoc pooled analyses support the safety
and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/day [23].
In conclusion, cariprazine offers a promising option for patients with schizophrenia, as it is associated with
minimal risk of causing weight gain and other metabolic side effects frequently seen with other
antipsychotics. While the underlying mechanisms of cariprazine's metabolic effects require further
investigation, its unique pharmacological profile provides insight into its favorable profile.
Cariprazine and treating schizophrenia-related psychosis
Cariprazine has emerged as a promising option for treating schizophrenia. The efficacy and safety of
cariprazine in schizophrenia have been evaluated in numerous short-term and long-term clinical trials,
which have shown significant improvements in symptomatology while maintaining good tolerability with
minimal side effects. These clinical studies are discussed in this section, and Table 1 below summarizes the
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 3 of 16
main clinical findings.
Clinical
trial
Number of
participants
Length
of
study
Type of
study
Endpoint
measurements
Treatment
arms Results Side effects
Durgam
et al,2016[25] 375 SixweeksRandomized,
double-blind,
placebo-
controlled,
proof-of-
concept trialPANNS CGI-SLow-dose
cariprazine
(1.5–4.5 mg/d),
high-dose (6–
12 mg/d),
placebo No significant
differences between
the two doses of
cariprazine and
placebo in PANSS
total score, change,
low-dose cariprazine
showed significantly
greater reductions in
PANSS scores
compared to placeboCariprazine was well-tolerated -
Similar percentages of AEs in all
groups (moderate and mild in
severity), most common AEs
akathisia (in both groups),
restlessness tremor, back pain,
and extrapyramidal disorder
Durgam
et al,2014[26] 732 SixweeksRandomized,
double-blind,
placebo- and
active-controlled,
fixed-dose
trial PANNS CGI-SCariprazine at
1.5 mg/d, 3.0
mg/d, or 4.5
mg/d,risperidone at
4.0 mg/d (for
assaysensitivity),
placebo Reduction in PANSS
and CGI-S scores
compared to placebo
for all active
treatments, with the
greatest improvement
observed with
cariprazine 4.5 mg/dCommon AEs were insomnia,
extrapyramidal disorder, akathisia,
sedation, nausea, dizziness, and
constipation. Mean changes in
metabolic parameters were small
and similar between treatment
groups
Durgam
et al,2015[27] 617 SixweeksRandomized,
double-blind,
placebo- and
active-controlled,
fixed-dose
trial PANNS CGI-SPlacebo,
cariprazine 3
mg/d,cariprazine 6
mg/d,aripiprazole 10
mg/d Cariprazine 3 and 6
mg/d showed
improvements relative
to placebo in PANSS
total and CGI-S scoresCommon AEs were Insomnia (all
groups), akathisia (cariprazine 6
mg/d), and headache (placebo,
cariprazine 6 mg/d)
Kane et
al., 2015
[24] 446 SixweeksRandomized,
double-blind,
placebo- and
active-controlled,
fixed-dose
trial PANNS CGI-SCariprazine 3-6
mg/d,cariprazine 6-9
mg/d, placeboImprovement in
PANSS and CGI-S
total scores in the
cariprazine arms
compared to placeboCariprazine was well-tolerated,
common AEs in both cariprazine
groups were akathisia,
extrapyramidal disorder, and
tremor; most were mild to
moderate in severity. Mean
metabolic changes were small and
similar between groups. Prolactin
levels decreased in all groups
Durgam,
2016[28] 765 97weeksDouble-blind,
placebo-
controlled,
parallel-
group studyTime to relapse
(worsening of
symptom scores,
psychiatric
hospitalization,
aggressive/violent
behavior, or
suicidal risk) Flexible or fixed
doses of
cariprazine (3,
6, or 9 mg/d,
depending on
the open-label
phase-fixed-
dosecariprazine or
placebo during
the double-
blind phaseTime to relapse was
significantly longer in
patients treated with
cariprazine than in
those treated with a
placebo, long-term
treatment with
cariprazine was safe
and could be used to
prevent relapse in
schizophrenia AEs during open-label treatment:
akathisia insomnia headache, no
cariprazine-related AEs observed
during double-blind treatment
Durgam,
2017[29] 93 48weeksOpen-label,
flexible-dose
trial PANSS CGI-SCariprazine
(1.5-4.5
mg/day) Long-term cariprazine
treatment was
deemed safe and well-
tolerated with no new
safety concerns
arising from long-term
treatment The most common AEs were
akathisia, insomnia, and weight
gain, with serious AEs occurring in
13%. Changes in metabolic
parameters were minimal and not
clinically significant. No prolactin
elevation or significant changes in
cardiovascular parameters
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Cutler,2018[30] 586 53weeksOpen-label,
flexible-dose
trial PANSS CGI-SCariprazine
doses ranging
from 3 to 9
mg/d Long-term treatment
with cariprazine at
doses up to 9 mg/d
was safe and well
tolerated in patients
with schizophrenia,
measures of efficacy
remained stable No unexpected safety issues or
deaths were reported. The most
commonly observed AEs were
akathisia, headache, insomnia,
and weight gain. Mean changes in
metabolic, hepatic, and
cardiovascular parameters were
not clinically relevant. Mean body
weight increased by 1.5 kg.
Prolactin levels decreased slightly
TABLE 1: Studies investigating the treatment of schizophrenia with cariprazine
PANSS: positive and negative syndrome scale, CGI-S: clinical global impression-severity scale, AEs: adverse events
In 2006, Durgam et al. at the Forest Research Institute conducted a phase 2 (NCT00404573) proof-of-concept
trial to evaluate the safety and efficacy of cariprazine in treating acute exacerbation of schizophrenia [25].
The six-week double-blind, placebo-controlled trial involved 375 participants who were randomly assigned
to receive either low-dose cariprazine (1.5-4.5 mg/day), high-dose (6-12 mg/day), or placebo. The primary
efficacy measure was the change in the Positive and Negative Syndrome Scale (PANSS) total score, with the
clinical global impression-severity (CGI-S) scale used as a secondary measure. While there were no
significant differences between the two doses of cariprazine in PANSS total score, low-dose cariprazine
showed significantly more significant reductions in PANSS total and PANSS negative scores compared to the
placebo. High-dose cariprazine had similar findings when compared to placebo. Notably, the study showed
similar percentages of patients in all three treatment groups reporting TEAEs. Most TEAEs were mild to
moderate in intensity. The only TEAEs reported in at least 5% of patients in either cariprazine group and
with an incidence of at least twice the rate in the placebo group during the double-blind treatment were
akathisia (in both groups), restlessness (in the 1.5-4.5 mg/day group), tremor (in the 1.5-4.5 mg/day group),
back pain (in the 1.5-4.5 mg/day group), and extrapyramidal disorder (in the 6-12 mg/day group) [25].
The findings suggest that treatment with cariprazine does not result in significantly different rates of TEAEs
compared to placebo, with most TEAEs being mild to moderate in intensity. However, specific side effects
such as akathisia, restlessness, tremor, and back pain in the cariprazine groups highlight the need for further
investigation into the EPS side effects of this medication. Notably, the incidence of extrapyramidal disorder
was higher in the higher dose group (6-12 mg/day) compared to the lower dose groups (placebo and 1.5-4.5
mg/day). This information is relevant for clinicians when considering the optimal dosing strategy for their
patients. Additionally, further research could explore the potential risk factors or predictors of developing
EPS side effects with cariprazine treatment. Such investigation could provide valuable information for
clinicians and patients in making informed decisions about the benefits and risks of this medication.
In 2017, Earley et al. conducted a groundbreaking multinational study (NCT00694707) to evaluate the safety
and efficacy of cariprazine compared to placebo and risperidone in treating acute exacerbation of
schizophrenia. This double-blind, randomized, placebo- and active-controlled, fixed-dose trial enrolled 732
patients who received six-week treatment with a two-week safety follow-up period [26]. The participants
were randomly assigned to receive either placebo, cariprazine at 1.5 mg/d, 3.0 mg/d, or 4.5 mg/d, or
risperidone at 4.0 mg/d. The study's primary outcome measure was the improvement in PANSS total score at
week six, which was statistically significant compared to placebo for all active treatments. The most
remarkable improvement was observed with cariprazine 4.5 mg/d, which substantially reduced the PANSS
total score of -10.4 [26]. Significant improvement was also observed in CGI-S for all active treatments. The
most common AEs reported were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness,
and constipation. However, mean changes in metabolic parameters were generally small and similar
between treatment groups, suggesting that cariprazine may have a favorable metabolic profile compared to
other antipsychotics [26]. Overall, this landmark study provides strong evidence for the efficacy and safety of
cariprazine in treating acute exacerbation of schizophrenia, with the highest dose (4.5 mg/d) showing the
most significant improvement in symptoms.
Between April 2010 and December 2011, Durgam et al. conducted a double-blind, randomized, placebo- and
active-controlled, fixed-dose study (NCT01104766) in multiple countries. Participants were randomly
assigned to receive either a placebo (n = 153) cariprazine 3 mg/d (n = 155), cariprazine 6 mg/d (n = 157), or
aripiprazole 10 mg/d (n = 152) for six weeks of treatment. The primary endpoint was the mean change from
baseline to week six in PANSS total score, with the secondary endpoint being the CGI-S score. Results
showed that both cariprazine 3 and 6 mg/d demonstrated statistically significant improvements relative to
placebo in PANSS total score change at week six (3 mg/d, -6.0; 6 mg/d, -8.8) and CGI-S scores (3 mg/d, -0.4; 6
mg/d, -0.5). Similarly, aripiprazole showed significant differences from the placebo on the PANSS (-7.0) and
CGI-S (-0.4). The most common TEAEs (≥ 10%) were insomnia (all groups), akathisia (cariprazine 6 mg/d),
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 5 of 16
and headache (placebo, cariprazine 6 mg/d). Overall, this study supports the efficacy, safety, and tolerability
of cariprazine 3 and 6 mg/d for treating acute exacerbation of schizophrenia [27].
In 2010, Kane et al. conducted a six-week, double-blind, placebo-controlled flexible-dose study
(NCT01104779) with 446 participants randomized to receive a placebo, cariprazine 3 to 6 mg/d, or
cariprazine 6 to 9 mg/d treatments [24]. The study evaluated primary and secondary efficacy measures,
including changes from baseline to week six in PANSS total and CGI-S. The results demonstrated significant
improvements compared to placebo for cariprazine 3 to 6 and 6 to 9 mg/d on the PANSS total score (3-6
mg/d: −6.8, 6-9 mg/d: −9.9) and CGI-S (3-6 mg/d: −0.3, P=0.012; 6-9 mg/d: −0.5) at week 6 [24]. Cariprazine
was well-tolerated, and common TEAEs in both cariprazine groups were mostly mild to moderate in severity
and included akathisia, extrapyramidal disorder, and tremor. Mean changes in metabolic parameters were
generally small and similar between groups, and prolactin levels decreased in all groups [24]. This study
further supports the potential of cariprazine 3 to 6 and 6 to 9 mg/d as an efficacious treatment for the acute
exacerbation of schizophrenia [24].
In a long-term study conducted by Durgam et al. (NCT01412060), the efficacy, safety, and tolerability of
cariprazine were evaluated for preventing relapse in adults with schizophrenia [28]. This multi-country,
double-blind, placebo-controlled study was conducted for up to 97 weeks. It consisted of five distinct phases:
screening, open-label run-in, stabilization, double-blind treatment (up to 72 weeks), and safety follow-up.
Patients were administered flexible or fixed doses of cariprazine (3, 6, or 9 mg/d, depending on the open-
label phase) and subsequently received either fixed-dose cariprazine or placebo during the double-blind
phase. Of the 765 patients, 264 completed open-label treatment, and 200 eligible patients were randomized
to a double-blind placebo (n=99) or cariprazine (n=101). The study showed that patients treated with
cariprazine had a significantly longer time to relapse than those treated with placebo, with relapse occurring
in only 24.8% of cariprazine-treated patients versus 47.5% of placebo-treated patients. During the open-
label treatment, the most commonly reported AEs were akathisia (19.2%), insomnia (14.4%), and headache
(12.0%). However, no cariprazine-related AEs of at least 10% were observed during double-blind treatment.
The study concluded that long-term treatment with cariprazine was more effective than placebo in
preventing relapse in patients with schizophrenia [28].
After successfully demonstrating the safety and efficacy of cariprazine in short-term clinical trials involving
patients with acute exacerbation of schizophrenia, Durgam et al. conducted an open-label extension study
(NCT00839852) to assess the long-term safety and tolerability of cariprazine in patients with schizophrenia
[29]. This study enrolled patients who had completed the previous six-week, randomized, placebo- and
active-controlled trial and had responded positively to treatment. Ninety-three patients received flexibly
dosed, open-label cariprazine (1.5-4.5 mg/day) for up to 48 weeks, with almost half of them completing the
full duration of treatment [29]. The study's most commonly reported AEs were akathisia, insomnia, and
weight gain, with 13% of patients experiencing serious AEs and 11% discontinuing treatment due to AEs.
Changes in metabolic parameters were minimal and not clinically significant, and no patient discontinued
treatment due to changes in metabolic parameters or body weight [29]. Using cariprazine did not lead to
prolactin elevation or significant changes in cardiovascular parameters. Overall, long-term treatment with
cariprazine was considered safe and well-tolerated in this 48-week, single-arm trial, with no new safety
concerns emerging from long-term treatment [29].
Cutler et al. conducted a multicenter, open-label, flexible-dose study to evaluate the safety and tolerability
of cariprazine in patients with schizophrenia for 53 weeks (NCT01104792) [30]. The trial included both new
patients and those who had participated in one of two phase 3 lead-in studies (NCT01104766,
NCT01104779), and 586 patients were treated with cariprazine. The completion rate was approximately 39%,
and there were no unexpected safety issues or deaths. The most common AEs were akathisia (16%),
headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73
(12.5%) patients discontinued the study due to AEs during open-label treatment [30]. The changes in
metabolic, hepatic, and cardiovascular parameters were not clinically significant. The mean body weight
increased modestly by 1.5 kg during the study, while prolactin levels decreased slightly, and efficacy
measures remained stable [30]. The study concluded that cariprazine treatment up to 9 mg/d was generally
safe and well tolerated in patients with schizophrenia over a long-term period [30].
It is important to note that researchers at the Forest Research Institute, an Allergan affiliate and
manufacturer of cariprazine, conducted these clinical trials. However, it is worth mentioning that these
studies were conducted per Good Clinical Practice guidelines and underwent rigorous evaluation by
regulatory agencies, such as the FDA, before approval. Overall, the available evidence suggests that
cariprazine is a safe and effective treatment option for schizophrenia, but further research is needed to
understand its long-term safety and efficacy fully. Table 1 summarizes the studies investigating cariprazine
for treating Schizophrenia.
Cariprazine for treating acute mania
Cariprazine has demonstrated remarkable efficacy in treating mania associated with bipolar disorder, as
evidenced by multiple clinical trials yielding consistently positive outcomes.
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 6 of 16
Durgam et al. (2015) conducted a phase 2 trial to evaluate the efficacy, safety, and tolerability of cariprazine
in treating acute manic or mixed episodes associated with bipolar I disorder [31]. The study was
multinational, randomized, double-blind, and placebo-controlled, involving 236 patients who received
cariprazine at a flexible dose of 3-12 mg/day after a washout period. After three weeks of double-blind
treatment, the primary and secondary efficacy parameters, the Young Mania Rating Scale (YMRS), and CGI-S
scores were assessed. The study found that cariprazine significantly reduced YMRS and CGI-S scores
compared to placebo, with each YMRS item showing a significant improvement from baseline to week 3 for
cariprazine. Moreover, a higher percentage of cariprazine patients met YMRS response (48% versus 25%) and
remission (42% versus 23%) criteria at week 3 than placebo patients [31].
The study found that patients treated with cariprazine had an overall mean daily dose of 8.8 mg/day and
experienced common AEs such as extrapyramidal disorder, headache, akathisia, constipation, nausea, and
dyspepsia. The discontinuation rate due to AEs was 14% for cariprazine patients compared to 10% for
placebo patients. Changes in metabolic parameters were similar between groups, except for fasting glucose
which increased significantly more in the cariprazine group than in the placebo group (p < 0.05). The Barnes
Akathisia Rating Scale and Simpson-Angus Scale showed that cariprazine patients were more likely to
experience treatment-emergent akathisia (22% versus 6% for placebo) and EPS (parkinsonism) (16% versus
1% for placebo) [31].
In the randomized, double-blind, placebo-controlled, multicenter, parallel-group phase 2/3 studies
conducted by Earley et al. (2018), adult patients between 18 and 65 years old with bipolar I disorder were
enrolled. Post hoc analyses evaluated the efficacy of cariprazine in treating manic episodes, as measured by
YMRS outcomes, including response (defined as a ≥50% decrease in score), remission (defined as a total
score of ≤12 and ≤8), cumulative remission, and global improvement. Additionally, the study investigated
composite remission, defined as a YMRS total score of ≤12 plus a Montgomery-Asberg Depression Rating
Scale (MADRS) total score of ≤12, as well as worsening/switch to depression, defined as a MADRS total score
of ≥15, every week [32]
In the study by Earley et al. (2018), significant improvements were observed in every measure evaluated for
cariprazine compared to placebo (P < .01 for all analyses), with a number needed to treat of ≤10 for each
measure. Furthermore, there was no evidence of worsening or a switch to depression. Although the study
had limitations, including post hoc analyses, short treatment duration, and the absence of an active
comparator, the results suggest that cariprazine can provide clinically significant relief for manic symptoms
in patients with bipolar I disorder. Additionally, it did not induce depressive symptoms [32].
McIntyre et al. (2019) conducted a study that aimed to compare the efficacy of cariprazine versus placebo in
patients with bipolar I disorder and mixed features. The review included data from three studies that
employed different criteria to determine efficacy, such as DSM-5 criteria and MADRS scores. The results
indicated that cariprazine was significantly more effective than placebo in reducing YMRS scores,
particularly in patients meeting the ≥10 MADRS criterion. Furthermore, cariprazine improved depressive
symptoms in the ≥10 MADRS group. More patients taking cariprazine met response and remission criteria
for YMRS, with the most significant results observed in the ≥10 MADRS group. However, the study had some
limitations, including being a post hoc analysis and the entry criterion o the MADRS scores <18, which could
potentially limit the assessment of MADRS changes. Overall, cariprazine showed efficacy in reducing both
manic and depressive symptoms in patients with mixed features, with varying efficacy based on specific
criteria [33].
In 2020, Pinto et al. conducted a rigorous meta-analysis to examine the efficacy of cariprazine, marketed as
cariprazine, in treating bipolar disorder. The study meticulously analyzed data from seven randomized
controlled trials, providing a comprehensive overview of the drug's therapeutic potential. The results of the
analysis were striking; cariprazine was found to be associated with a moderate yet significant reduction in
manic symptoms, as measured by the YMRS change scores. Moreover, the drug significantly increased
remission and response rates for both manic and mixed episodes compared to the placebo. This finding
underscores the potential of cariprazine as a promising treatment option for bipolar disorder, offering hope
to individuals suffering from this debilitating condition [34].
The comprehensive meta-analysis conducted by Pinto et al. (2020) demonstrated the safety and
effectiveness of cariprazine in treating acute manic and mixed episodes associated with bipolar disorder. In
terms of depressive symptoms, the use of cariprazine at daily doses of 1.5 mg and 3 mg demonstrated a
modest yet significant improvement, based on MADRS scores. Although the drug was associated with
adverse effects, it did not result in higher dropout rates due to adverse effects compared to the placebo. In
addition, the study revealed that cariprazine at doses of 1.5-3 mg daily is efficacious in treating acute bipolar
depression, albeit with smaller effect sizes. The findings of this meta-analysis provide strong evidence for
the use of cariprazine in managing the symptoms of bipolar disorder [34].
In 2015, Calabrese et al. conducted a phase 3 trial to assess the efficacy, safety, and tolerability of
cariprazine in treating patients with acute manic or mixed episodes related to bipolar I disorder. The trial
comprised 497 randomized into three groups: placebo, cariprazine 3-6 mg/d, or cariprazine 6-12 mg/d for
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 7 of 16
three weeks of double-blind treatment [35].
The study found that low- and high-dose cariprazine was significantly more effective than placebo in
reducing manic symptoms, as assessed by the YMRS total score. The difference in the least squares means
change from baseline to week 3 in the YMRS total score favored both cariprazine treatment groups over
placebo (LSMD [95% CI]: 3-6 mg/d, -6.1 [-8.4 to -3.8]; 6-12 mg/d, -5.9 [-8.2, -3.6]; P < .001 [both]).
Additionally, both cariprazine treatment groups showed statistically significant superiority to the placebo
on all 11 YMRS single items [35].
In addition to reducing manic symptoms, the study found that cariprazine treatment was associated with
significant improvement in the CGI-S of Illness scores when compared to placebo. Treatment-related AEs,
including akathisia, nausea, constipation, and tremor, were generally manageable, with akathisia being the
most common. Despite this, cariprazine was both effective and well-tolerated for treating acute manic or
mixed episodes associated with bipolar I disorder, with the caveat that the incidence of akathisia was higher
in the cariprazine group than in the placebo group [35].
Overall, the collective evidence from multiple randomized controlled trials supports the effectiveness of
cariprazine in treating mania associated with bipolar disorder. These studies have consistently
demonstrated significant improvements in manic symptoms, with fewer AEs. Additionally, cariprazine has
shown promise in preventing the recurrence of manic or mixed episodes over the long term. These findings
underscore the potential value of cariprazine as a treatment option for patients with bipolar disorder who
experience manic or mixed episodes. Table 2 summarizes the studies investigating the treatment of mania
with cariprazine.
Clinical
trial
Number of
participants
Length of
study
Type of
study
Endpoint
measurements Treatment arms Results Side effects
Durgam
et al.,2015 [31]236 ThreeweeksDouble-
blind,placebo-
controlled
study YMRS, CGI-SCariprazine at a
flexible dose of 3-12
mg/day after
washout, placeboCariprazine was found to significantly reduce
manic or mixed episodes associated with
bipolar I disorder, as measured by YMRS and
CGI-S scores. A higher percentage of patients
treated with cariprazine met YMRS response
and remission criteria at week 3 compared to
placebo patients. Common AEs
associated with
cariprazine
included
extrapyramidal
disorder,
headache,
akathisia,
constipation,
nausea, and
dyspepsia, and
treatment-
emergent
akathisia and
EPS(parkinsonism)
were more
likely to occur in
cariprazine
patients.
Earley et
al., 2017
[32] 1065 ThreeweeksPost hoc
analysis of
threerandomized,
double-
blind,placebo-
controlled,
multicenter,
parallel-
groupphase 2/3
studies YMRS In two of the trials
(RGH-MD-31 and
RGH-MD-32), a
flexible-dose design
with cariprazine
doses of 3-12 mg/d
was used; in the
third trial (RGH-MD-
33), a fixed/flexible-
dose design with
two cariprazine-
treatment arms (3-6
mg/d or 6-12 mg/d)
was used. All
cariprazine doses
were pooled for post
hoc analyses. Cariprazine was found to be significantly more
effective than placebo in every measure
evaluated (P < .01 for all analyses), with a
number needed to treat of ≤10 for each
measure. Cariprazine did not induce depressive
symptoms and may provide clinically significant
relief for manic symptoms in patients with
bipolar I disorder. None
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McIntyre
et al.,2019 [33]1037 ThreeweeksPost hoc
analysis of
data from
threesimilarly-
designed
trials of
cariprazine
compared to
placebo MADRS,
YMRS Placebo, cariprazine
3.0-6.0 mg/d, or 6.0-
12.0 mg/d Cariprazine was significantly more effective than
placebo in reducing YMRS scores, particularly
in patients meeting the ≥10 MADRS criterion.
Cariprazine improved depressive symptoms in
the ≥10 MADRS group. More patients taking
cariprazine met response and remission criteria
for YMRS, with the most significant results
observed in the ≥10 MADRS group. None
Pinto et
al., 2020
[34] Sevenstudies Numerous
timelines
were used
in themeta-analysisMeta-analysis MADRS,
YMRS Numerous doses of
cariprazine were
compared to a
placebo in this meta-
analysis The study showed that cariprazine is safe and
effective in treating acute manic and mixed
episodes associated with bipolar disorder. The
study also found that cariprazine at 1.5-3 mg
daily can effectively treat acute bipolar
depression, although with smaller effect sizes.
The meta-analysis provides strong evidence for
the use of cariprazine in managing the
symptoms of bipolar disorder. None
Calabrese
et al.,2014 [35]497 ThreeweeksDouble-
blind,placebo-
controlled
study YMRS, CGI-SPlacebo, cariprazine
3-6 mg/d, or
cariprazine 6-12
mg/d Calabrese et al. conducted a phase 3 trial in
2014 to assess the efficacy, safety, and
tolerability of cariprazine in treating acute manic
or mixed episodes related to bipolar I disorder.
The study found that low- and high-dose
cariprazine was significantly more effective than
placebo in reducing manic symptoms, as
measured by the YMRS total score, and also
demonstrated significant improvement in the
CGI-S scores compared to placebo. Despite the
manageable incidence of treatment-related AEs,
such as akathisia, nausea, constipation, and
tremor, cariprazine was effective and well-
tolerated for treating acute manic or mixed
episodes associated with bipolar I disorder. The most
common
treatment-
related AEs
associated with
cariprazine
weremanageable
and included
akathisia,
nausea,
constipation,
and tremor.
TABLE 2: Studies investigating the treatment of mania with cariprazine
YMRS: Young Mania Rating Scale, CGI-S: clinical global impression-severity scale, MADRS: Montgomery-Asberg depression rating
scale, EPS: extrapyramidal symptoms, AEs: adverse events
Cariprazine for treating bipolar depression
Bipolar depression is a common and debilitating condition affecting millions worldwide. Cariprazine has
been studied extensively for its efficacy in treating bipolar depression. In this section, we will review the
clinical trials that demonstrated the efficacy of cariprazine in treating bipolar depression.
In 2009, Yatham et al. conducted a phase 2 clinical trial (NCT00852202) to evaluate the efficacy, safety, and
tolerability of cariprazine versus placebo for depressive episodes associated with bipolar I or II disorder
(Yatham, 2020). This eight-week, double-blind, placebo-controlled, fixed/flexible-dose study enrolled 234
patients randomized in a 1:1:1 ratio to placebo, "low-dose" cariprazine (0.25-0.5 mg/day), or "high-dose"
cariprazine (1.5-3.0 mg/day) [36]. The primary endpoint was the change in the MADRS total scores from
baseline to week eight. The secondary endpoint was the mean clinical global impressions-improvement
score at week eight. The study found that neither the low-dose nor high-dose cariprazine group showed
significant differences from the placebo group. Nonetheless, this trial provided useful information that was
utilized in the design and implementation of subsequent phase 2b/3 clinical trials of cariprazine in bipolar
depression. No new safety concerns were observed with cariprazine, and the most common TEAEs (≥5% of
cariprazine patients and twice the rate of placebo) included insomnia, akathisia, dry mouth, nausea, weight
increase, diarrhea, restlessness, vomiting, musculoskeletal stiffness, migraine, and cough. Metabolic and
weight changes were generally comparable between the cariprazine and placebo groups [36].
In 2016, Durgam et al. conducted a phase 2 clinical trial (NCT01396447) to evaluate the efficacy, safety, and
tolerability of cariprazine for major depressive episodes associated with bipolar I disorder. The trial was a
multinational, multicenter, double-blind, placebo-controlled, parallel-group, fixed-dose study, involving
adult patients who received either placebo or cariprazine at doses of 0.75, 1.5, or 3.0 mg/day for eight weeks
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 9 of 16
[37]. The study included 571 patients, and the primary and secondary efficacy endpoints were the change in
the MADRS and CGI-S scores, respectively. Results showed that cariprazine at 1.5 mg/day significantly
improved MADRS total score compared with placebo (least squares mean difference = -4.0, 95% CI=-6.3, -1.6;
adjusted for multiple comparisons). However, cariprazine at 3.0 mg/day showed a reduction in the MADRS
score that was not statistically significant when adjusted for multiple comparisons. The 0.75 mg/day dosage
was similar to placebo. A similar pattern for significance was observed on the CGI-S. The most common AEs
(≥10%) in cariprazine-treated patients were akathisia and insomnia, and weight gain was slightly higher
with cariprazine than with placebo. The study concluded that cariprazine at 1.5 mg/day demonstrated
consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting its
efficacy for treating bipolar I depression [37].
In 2016, a multinational, a six-week long, phase 3 double‐blind placebo‐controlled trial (NCT02670538) was
conducted to evaluate the efficacy and safety of cariprazine in adult patients with bipolar I disorder and a
current depressive episode [38]. A total of 493 patients were randomized to receive either placebo (n=167),
cariprazine 1.5 mg/day (n=168), or cariprazine 3.0 mg/day (n=158). The primary efficacy endpoint was the
change from baseline to week six in the MADRS total scores, and the secondary endpoint was the change in
the CGI-S scores compared to the placebo (Earley, 2020). The results showed that cariprazine 1.5 mg/day
significantly reduced depressive symptoms compared to placebo, both in primary (MADRS LSMD=-2.5;
adjusted P=.0417) and secondary (CGI-S LSMD=-0.3; adjusted P=.0417) efficacy measures. However, the
differences were not statistically significant for cariprazine 3.0 mg/day. The most common TEAEs were
akathisia, restlessness, nausea, and fatigue. The study also found that the mean metabolic parameter
changes were low and generally comparable among groups, and mean weight increases were ≤0.5 kg for all
groups. Overall, the safety and tolerability profiles of cariprazine were similar to previous studies [38].
A subsequent phase 2 clinical trial was designed to build on the findings of a previous study and evaluate the
efficacy and safety of cariprazine at doses of 1.5 mg/day and 3.0 mg/day versus placebo in treating adults
with bipolar I depression (NCT02670551) [39]. The trial was a randomized, double-blind, fixed-dose study
that included 488 patients randomized to receive either cariprazine 1.5 mg/day, cariprazine 3.0 mg/day, or a
placebo. The primary efficacy endpoint was the change from baseline to week six in the MADRS total score.
Both cariprazine groups showed significant reductions in MADRS total scores compared to placebo, with the
1.5 mg/day group showing a reduction of -2.5 (95% CI: -4.6 to -0.4; adjusted p = 0.033) and the 3.0 mg/day
group showing a reduction of -3.0 (95% CI: -5.1 to -0.9; p = 0.010). MADRS response rates only reached
statistical significance for the cariprazine 3.0 mg/day group (51.8%, NNT = 8, p = 0.024) (Earley, 2019).
However, both cariprazine groups had significantly higher MADRS remission rates (33.1%, NNT = 10, p =
0.037 for the 1.5 mg/day group and 32.3%, NNT = 11, p = 0.039 for the 3.0 mg/day group) [39]. Overall, these
findings were consistent with those of previous phase 2 and 3 trials, demonstrating the efficacy of both 1.5
mg/day and 3.0 mg/day doses of cariprazine in achieving the primary endpoint and lower CGI-S scores than
placebo. Moreover, both doses showed good tolerability profiles, low discontinuation rates, and no clinically
significant metabolic changes or weight gain [39].
A pooled post hoc analysis by Mcintyre et al. aimed to evaluate the efficacy of cariprazine in the treatment
of bipolar depression with or without concurrent manic symptoms [40]. This study aimed to evaluate the
efficacy of cariprazine in treating bipolar I depression with or without manic symptoms. The study included
patients from three randomized, double-blind, placebo-controlled trials who met DSM-IV-TR or DSM-5
criteria for bipolar I disorder with a current major depressive episode and had concurrent manic symptoms
by a baseline YMRS total score of least 4. The efficacy of cariprazine 1.5 and 3 mg/day doses was compared
to placebo. The analysis included the least squares mean change from baseline to week six in the MADRS
total score. The study included 1383 randomized to treatment, with 808 (58.4%) having concurrent manic
symptoms. For patients with manic symptoms, cariprazine 1.5 and 3 mg/day significantly reduced the mean
MADRS total score from baseline to week six compared to the placebo, respectively. For patients without
manic symptoms, the LSMD was significant for 1.5 mg/day (-3.3; p = .0008) but not for 3 mg/day (-1.9; p =
.0562). This post hoc analysis suggests that cariprazine may be an appropriate treatment option for patients
with bipolar I depression with or without manic symptoms. Higher doses are potentially more effective in
patients with manic symptoms [40].
Taken together, these five trials demonstrate the efficacy of cariprazine in treating bipolar depression.
Cariprazine appears well-tolerated, with the most common AEs being akathisia, restlessness, and nausea.
Further studies are needed to confirm these findings and to explore the long-term safety and efficacy of
cariprazine in treating bipolar depression. Table 3 summarizes the studies investigating the treatment of
bipolar depression with cariprazine.
Clinical trial
identification
number and
reference
Number of
participants
Length
of
study
Type of
study
Endpoint
measurements
Treatment
arms Results Side effects
No new safety signals were
observed with cariprazine,
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 10 of 16
Yatham et al.,
2020 [36] 234 EightweeksDouble-
blind,placebo
study MADRS CGI-SPlacebo,
"low-dose"
cariprazine
(0.25-0.5
mg/day),
or "high-
dose"cariprazine
(1.5-3.0
mg/day)Neither the low-dose nor high-dose
cariprazine group showed significant
differences from the placebo group in the
primary endpoint of change in MADRS total
scores from baseline to week eight. The
study helped to identify factors that may have
influenced this outcome, which helped to
design and conduct subsequent clinical trials
of cariprazine in bipolar depression. and the most common
TEAEs were generally
similar between the
cariprazine and placebo
groups. The most common
TEAEs (≥5% of cariprazine
patients and twice the rate
of placebo) included
insomnia, akathisia, dry
mouth, nausea, weight
increase, diarrhea,
restlessness, vomiting,
musculoskeletal stiffness,
migraine, and cough.
Durgam et
al., 2011 [37]571 EightWeeksDouble-
blind,placebo-
controlled,
parallel-
group, fixed-
dose studyMADRS CGI-Splacebo or
cariprazine
at 0.75,
1.5, or 3.0
mg/dayCariprazine at 1.5 mg/day significantly
improved MADRS total score compared with
placebo. Cariprazine at 3.0 mg/day showed
a greater reduction in MADRS score than
placebo, but it was not statistically significant
when adjusted for multiple comparisons. The
0.75 mg/day dosage was similar to the
placebo. A similar pattern for significance
was observed on the CGI-S. The study
concluded that cariprazine at 1.5 mg/day
demonstrated consistent efficacy compared
with placebo across outcomes and was
generally well-tolerated, suggesting its
efficacy for treating bipolar I depression. The most common AEs
(≥10%) in cariprazine-
treated patients were
akathisia and insomnia, and
weight gain was slightly
higher with cariprazine than
with placebo.
Earley et al.,
2020 [38] 493 SixweeksFixed-dose,
randomized,
controlled
trial MADRS CGI-Scariprazine
at 1.5mg/day
and 3.0
mg/day
compared
withplacebo-Cariprazine 1.5 mg/day significantly reduced
depressive symptoms compared to placebo,
both in primary (MADRS LSMD=-2.5;
adjusted P=.0417) and secondary (CGI-S
LSMD=-0.3; adjusted P=.0417) efficacy
measures. However, the differences were
not statistically significant for cariprazine 3.0
mg/day. -The study also found that the mean
metabolic parameter changes were low and
generally comparable among groups, and
mean weight increases were ≤0.5 kg for all
groups. -Overall, the safety and tolerability
profiles of cariprazine were similar to
previous studies. The most common TEAEs
were akathisia,
restlessness, nausea, and
fatigue.
Earley et al.,
2019 [39] 488 SixweeksFixed-dose,
randomized,
controlled
trial MADRS CGI-Scariprazine
at 1.5mg/day,
3.0mg/day
andplacebo-Both cariprazine doses significantly reduced
MADRS total scores from baseline to week 6
compared to placebo -MADRS remission
rates were significantly higher in both
cariprazine groups, while response rates
only reached statistical significance for the
cariprazine 3.0 mg/day group -The study
concluded that both 1.5 mg/day and 3.0
mg/day doses of cariprazine were effective in
achieving the primary endpoint when
compared to placebo, and CGI-S scores
were lower in cariprazine groups compared
to placebo Cariprazine had good
tolerability profiles, low rates
of discontinuation, and no
clinically significant
metabolic changes or
weight gain.
McIntyre et
al., 2020 [40]1383 SixweeksThreerandomized,
double-
blind, MADRS cariprazine
1.5 and 3
mg/day
doses -Cariprazine effectively reduced the MADRS
total score in patients with bipolar I
depression and concurrent manic symptoms
compared to placebo. -Both 1.5 and 3
mg/day doses of cariprazine effectively
reduced MADRS total score in patients with
concurrent manic symptoms. -Cariprazine
1.5 mg/day also effectively reduced MADRSNone
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 11 of 16
placebo-
controlled
trials werecompared
to placebototal score in patients without concurrent
manic symptoms. -These results suggest
that cariprazine may be a suitable treatment
option for patients with bipolar I depression,
with higher doses potentially being more
effective in patients with concurrent manic
symptoms.
TABLE 3: Studies investigating the treatment of bipolar depression with cariprazine
CGI-S: clinical global impression-severity scale, MADRS: Montgomery-Asberg depression rating scale, TEAEs: treatment-emergent adverse events,
AEs: adverse events At the time of writing, there are three clinical trials on the efficacy and safety of cariprazine in bipolar
disorder that are currently ongoing and registered on ClinicalTrials.gov. One of these is a randomized
controlled trial that aims to evaluate the efficacy and safety of cariprazine in treating pediatric patients with
bipolar I depression (NCT04777357). Another is an open-label study that will assess the long-term safety
and tolerability of cariprazine in pediatric patients with schizophrenia or bipolar I disorder for 26 weeks
(NCT04578756). Lastly, a randomized controlled trial aims to investigate relapse prevention in bipolar I
patients with manic or depressive episodes, with or without mixed features (NCT03573297). However, it is
essential to note that the preliminary findings of these ongoing clinical trials are not yet available, and
further research is needed to fully understand the safety and efficacy of cariprazine in the treatment of
bipolar disorder.
Cariprazine as an adjuvant for treating unipolar depression
After a few phase 2 and phase 3 human clinical trials, cariprazine was recently approved for adjunctive
treatment of major depressive disorder (MDD) in adults who had not responded adequately to
antidepressant monotherapy [13]. Cariprazine had demonstrated antidepressant-like properties in several
animal behavior models during preclinical trials [41]. This section will discuss some clinical trials evaluating
cariprazine's efficacy in the treatment of unipolar depression.
In a randomized, double-blind, placebo-controlled, flexible-dose study, Durgam et al. investigated the
efficacy and safety of adjunctive treatment with cariprazine in adults with MDD who had an inadequate
response to standard antidepressants (NCT01469377) [42]. The study was conducted from December 2011 to
December 2013. A total of 819 eligible patients were randomized to receive either placebo (n = 269),
cariprazine 1-2 mg/day (n = 274), or cariprazine 2-4.5 mg/day (n = 276) for 8 weeks. The primary efficacy
parameter was the change in the MADRS total score from baseline to week eight. The study found that
adjunctive cariprazine 2-4.5 mg/day was significantly more effective than placebo in reducing MADRS total
score at week eight (least squares mean difference [LSMD] = -2.2; adjusted P = .0114), but cariprazine 1-2
mg/day did not show significant improvement compared to placebo (LSMD = -0.9; adjusted P = .2404) [42].
Significant LSMDs were observed in the 2-4.5 mg/day group at all earlier study visits (weeks two, four, and
six) and in the 1-2 mg/day group at weeks two and four (all P values < .05). The study concluded that
adjunctive cariprazine 2-4.5 mg/day was effective and generally well-tolerated in adults with MDD who had
inadequate responses to standard antidepressants [42].
After this trial, a phase 3 randomized, double-blind, placebo-controlled trial that lasted 18 to 19 weeks
(NCT01715805) was conducted to further evaluate the efficacy of cariprazine (1.5-4.5 mg/day) as an
adjunctive treatment to antidepressant therapy (ADT) for MDD [43]. In this study, during an eight-week
open-label period, ADT response was assessed, and inadequate responders were randomized (N = 530) to
open-label ADT plus placebo (n = 261) or cariprazine (n = 269) for the eight-week double-blind phase.
Results showed that cariprazine did not significantly improve MADRS scores compared to placebo ([LSMD]: -
0.2, P = 0.7948 and SDS LSMD: -0.7, P = 0.2784). However, cariprazine did improve CGI-I scores (LSMD: -0.2;
P = 0.0410) versus placebo. The results of this study contrasted with previously published results [43].
To further evaluate the safety of cariprazine plus adjunctive ADT in patients with MDD, a long-term, open-
label study (NCT01838876) was also carried out [44]. In this study, some participants had previously
participated in the negative eight-week study above (n=311) (NCT01715805), while others were newly
enrolled and had no prior exposure to cariprazine (n=131). Of the patients who continued in the study, a
higher percentage of continuing patients (66.2%) completed the study than new patients with no prior
exposure to cariprazine (35.9%). AEs were reported in 79% of patients, with the most common being
akathisia (15.9%) and headache (11.6%). The mean changes in cardiovascular and ophthalmologic
parameters were generally not clinically significant. The study showed that cariprazine was generally safe
and well tolerated as adjunctive therapy to treat MDD, with a remission rate of 53.3% by week 26. Serious
AEs occurred in 2% of patients, and two deaths occurred (one traffic accident and one completed suicide,
both considered unrelated to treatment) [44].
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 12 of 16
Fava et al. also conducted a long term double-blind, placebo-controlled, randomized phase 2 study which
lasted 19 weeks to evaluate the efficacy, safety, and tolerability of adjunctive cariprazine at doses of 0.1-0.3
and 1.0-2.0 mg/day for treating treatment-resistant MDD in adults (NCT00854100) [45]. A total of 231
patients were randomized. The primary and secondary endpoints were the change in MADRS CGI-S total
scores. Although none of the predefined parameters reached significance for either dose of cariprazine,
higher doses were associated with numerically more significant mean changes in MADRS and CGI-S scores
and MADRS response and remission rates, respectively, to placebo [45]. No significant differences were
observed between cariprazine 0.1-0.3 mg/day and placebo. Although not statistically significant, the MADRS
response rates observed in patients taking cariprazine 1.0-2.0 mg/day exceeded the 10% threshold typically
clinically significant [45]. The mean difference in responders between cariprazine and placebo (12.5%) was
higher than the difference observed in the first trial for cariprazine 2.0-4.5 mg/day (11.1%) discussed above
[42].
A post hoc analysis of a phase 3 clinical trial (NCT03738215) assessing the efficacy of cariprazine as an
adjunctive to ADT in improving depressive symptoms in various patient subgroups was published by
Papakostas et al. in 2023 [46]. The trial involved 759 patients who were randomized to receive placebo + ADT,
cariprazine 1.5 mg/d + ADT, or cariprazine 3 mg/d + ADT for six weeks of double-blind treatment. The
subgroups in this trial were categorized based on their level of response to ongoing ADT at baseline and the
number of ADT failures during the current episode. The post hoc analyses demonstrated that cariprazine
(1.5 mg/d and 3 mg/d) + ADT reduced MADRS score significantly compared to ADT+ placebo and was
effective in lowering MADRS total score regardless of the level of response to ongoing ADT at baseline or the
number of prior ADT failures in the current episode [46].
In a recent post hoc analysis, Thase et al. collected and analyzed the results of all previous clinical trials to
evaluate the long-term safety, tolerability, and efficacy of cariprazine as an adjunctive treatment for patients
with MDD who had an inadequate response to ADT [47]. In total, results from 2,222 participants who had
previously received treatment with cariprazine in a placebo-controlled or open-label study were collected.
The results showed that cariprazine is generally safe and well-tolerated. Treatment-emergent AEs occurred
in 61% of cariprazine-treated patients and 48% of placebo-treated patients. The most common AEs were
akathisia (11% in cariprazine-treated patients and 2% in placebo-treated patients) and restlessness (6% in
cariprazine-treated patients and 2% in placebo-treated patients). Discontinuation due to an AE occurred in
6% of cariprazine-treated patients and 2% of placebo-treated patients [47].
The changes in metabolic parameters, including shifts in fasting glucose and lipid parameters, were similar
in cariprazine- and placebo-treated patients [47]. In the long-term safety study, the mean weight change was
1.6 kg over six months. Other safety endpoints, including laboratory and C-SSRS assessments of suicidality,
were generally consistent with the safety profile of cariprazine in approved indications of bipolar disorder
and schizophrenia [47].
While this recent post hoc analysis revealed no new safety signals and the data is consistent with the
currently approved prescribing information, as with all medications, the benefits and risks should be
carefully evaluated individually. Patients should be closely monitored for AEs during treatment.
Limitations and drawbacks of cariprazine
It is essential to consider the limitations and drawbacks of cariprazine when deciding its use in treating
psychiatric conditions. While numerous studies have shown cariprazine to be effective in treating bipolar
mania and depression, others have suggested that it may not be a good choice for certain patients or may be
associated with adverse effects. For example, a study published in the Journal of Psychopharmacology found
that cariprazine may not be effective in treating psychosis associated with Parkinson's disease and may even
worsen some symptoms [48]. Additionally, cariprazine may be associated with a risk of akathisia, a condition
characterized by restlessness, agitation, and an inability to sit still [40-45,48] . Patients taking cariprazine
should be monitored closely for signs of akathisia and other adverse effects. It is crucial to weigh the
potential benefits and risks of cariprazine when deciding its use in treating psychiatric conditions. While
some patients may benefit from this medication, others may not respond well or experience adverse effects.
While several clinical trials have investigated the safety and efficacy of cariprazine for treating psychiatric
disorders, most of these studies have only compared it to a placebo. Consequently, there is a critical need for
additional head-to-head trials that directly compare cariprazine to other commonly used SGAs, such as
Seroquel or Olanzapine. These studies are essential in establishing the relative effectiveness and safety of
cariprazine compared to other frequently prescribed antipsychotic medications. Furthermore, they can
provide valuable information to clinicians and patients to make informed decisions about the most
appropriate treatment options for their needs.
Head-to-head trials can contribute significantly to developing treatment guidelines and formulary decisions
made by healthcare organizations. Although cariprazine has demonstrated promising results in clinical trials
against placebo, further research comparing its effectiveness and safety to other SGAs in head-to-head trials
is crucial to establish its relative benefits and risks. Therefore, conducting such studies is imperative to
improve the current understanding of cariprazine's potential in treating psychiatric disorders and to guide
2023 Tarzian et al. Cureus 15(5): e39309. DOI 10.7759/cureus.39309 13 of 16
clinical decision-making.
Conclusions
Mood disorders, including major depression and bipolar disorder, and psychotic disorders, such as
schizophrenia, are complex and challenging mental illnesses that can significantly impact an individual's
daily functioning and quality of life. While the prevalence of these disorders varies, they are all considered a
significant burden to global health. The emergence of atypical antipsychotic agents in the late 1990s
revolutionized the management of these disorders, providing a broad-spectrum efficacy previously
unavailable. However, these agents have significant concerns regarding their side effect profiles, leading to
a shift in focus toward identifying atypical agents with a more favorable profile. Cariprazine is one such
agent that has demonstrated a unique mechanism of action and favorable safety profile, making it a
promising medication for managing a spectrum of mental health conditions. This review has provided a
thorough analysis of cariprazine's efficacy and safety profile, which will be helpful for clinicians and
researchers.
Appendices
The ChatGPT language model (OpenAI, San Francisco, California) was utilized to assist in editing and
rewording the work to ensure coherence and clarity in conveying the findings (Figure 1).
FIGURE 1: ChatGPT-assisted editing and rewording of the review article
Additional Information
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Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
The authors wish to acknowledge ChatGPT for assisting with the editing of this paper.
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