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Med Sci Monit
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Medical Science Monitor
Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
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10.12659/MSM.945411
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Review Articles
Cariprazine in Psychiatry: A Comprehensive Review of Efficacy, Safety, and Therapeutic Potential
Koziej Sylwia https://orcid.org/0009-0002-9607-6693
1ABDEF
Kowalczyk Emilia https://orcid.org/0000-0001-7687-8870
1ABDEF
Soroka Ewelina https://orcid.org/0000-0001-6909-2749
2AE
1 II Department of Psychiatry and Psychiatric Rehabilitation, Student Scientific Circle, Faculty of Medicine, Medical University of Lublin, Lublin, Poland
2 II Department of Psychiatry and Psychiatric Rehabilitation, Faculty of Medicine, Medical University of Lublin, Lublin, Poland
Corresponding Author: Sylwia Koziej, e-mail: skoziej152@gmail.com
A Study Design

B Data Collection

C Statistical Analysis

D Data Interpretation

E Manuscript Preparation

F Literature Search

G Funds Collection

2024
20 9 2024
14 8 2024
30 e945411-1e945411-7
05 6 2024
09 7 2024
© Med Sci Monit, 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
This article provides a comprehensive review of recent developments regarding a new atypical antipsychotic drug – cariprazine – considering the mechanism of action, efficacy, safety, and promising therapeutic option for various psychiatric disorders, including schizophrenia and bipolar disorder, therapy of addictions, and treatment in the pediatric population. Its distinct pharmacological profile, characterized by partial agonism at dopamine D2 and D3 receptors, as well as serotonin receptors – 5HT1A with a preference for the D3 receptor – sets it apart from other antipsychotics. The unique mechanism of action contributes to cariprazine’s positive impact on negative symptoms in schizophrenia and an antidepressant effect. Its relatively low risk of adverse effects, such as sedation, metabolic issues, and hypotension, enhances its tolerability. In bipolar affective disorder, cariprazine exhibits effectiveness in managing both depressive and manic episodes. Ongoing research in pediatric populations suggests potential benefits in schizophrenia, bipolar I disorder, and autism spectrum disorder, but further research is necessary to establish safety and efficacy. Moreover, cariprazine shows promise in addiction therapy, particularly with coexisting psychiatric disorders. Continued research and clinical exploration may discover additional insights, broadening its use in diverse patient populations.

This article aims to review the role of cariprazine, a dopamine D2/D3 and serotonin 5-HT1A receptor partial agonist, in the management of psychotic illnesses, including schizophrenia, bipolar disorder, addiction therapy, and pediatric treatment.

Cariprazine
Antipsychotic Agents
Schizophrenia
Bipolar Disorder
==== Body
pmcIntroduction

The 3 main symptom domains of schizophrenia and schizoaffective disorder are positive, negative, and cognitive symptoms. Delusions, hallucinations, and disorganized thought patterns are examples of positive symptoms; anhedonia, avolition, asociality, dulled affect, and alogia are examples of negative symptoms [1]. Cognitive symptoms, such as memory problems and attention and perception defects, are common, in addition to the positive and negative symptom manifestations of schizophrenia [2,3]. The cognitive symptoms and, above all, the negative symptoms, of schizophrenia significantly impair patients’ daily functioning and quality of life [4]. Increased dopamine synthesis and dopamine changes have been associated with psychotic features in both disorders. Therefore, the primary drugs for treatment of schizophrenia are dopamine antagonists and/or 5HT modulators [5]. Nevertheless, these medications exhibit a considerable range of adverse effects and have a less pronounced impact on negative symptoms [6]. Therefore, antipsychotics acting as partial dopamine D3 receptor agonists, particularly cariprazine, may be a good option for improving cognitive faculties and negative symptoms in patients with refractory schizophrenia and its severe course. The beneficial effect of cariprazine is significantly stronger compared to other generations of antipsychotics in both animal and human studies [7,8].

Bipolar disorder (BD) is characterized by episodes of depression, mania/hypomania, or mixed episodes [9,10]. The clinical presentation of bipolar disorder is diverse, making the selection of appropriate and effective treatment difficult and complex [11]. The primary objective of treating bipolar disorder is to achieve euthymia and prevent relapses. This treatment typically involves the use of mood-stabilizing medications, such as lithium, valproic acid, carbamazepine, or lamotrigine, as well as atypical antipsychotic drugs [12–14]. Given the long-term nature of this treatment, it necessitates good patient cooperation, particularly because certain medications require monitoring the function of other organs, including the kidneys, thyroid gland, and blood count [15]. In the treatment of depression in bipolar affective disorder, traditional antidepressants are often employed [16]. However, clinical research indicates their limited effectiveness and an association with mania or hypomania. Consequently, atypical antipsychotic medications in combination with mood stabilizers have been registered for use in therapy [15].

This article reviews the role of cariprazine, a dopamine D2/D3 and serotonin 5-HT1A receptor partial agonist, in the management of psychotic illness, including schizophrenia.

Mechanism of Action of Cariprazine

Cariprazine is a new atypical antipsychotic drug. Currently, second- and third-generation antipsychotic drugs are classified as atypical. Second-generation drugs include risperidone, lurasidone, clozapine, olanzapine, and quetiapine, whereas third-generation drugs include aripiprazole and cariprazine [17]. Atypical antipsychotic drugs, compared to classical (typical) medications, are less likely to cause unwanted effects such as dyskinesia and other extrapyramidal adverse effects [18]. However, atypical antipsychotics have been linked to metabolic dysfunction, including diabetes and significant weight gain. The mechanism of action of cariprazine is rooted in its interaction with dopamine and serotonin receptors. It functions as a partial agonist at dopamine D2 and D3, as well as serotonin 5HT1A receptors, with a preference for binding to the D3 receptor. Cariprazine acts as an antagonist at 5-HT2 and histamine H1 receptors, with no affinity for muscarinic cholinergic receptors [6,9,19]. Due to partial agonism of D3 receptors located in the limbic system, cariprazine can affect the negative symptoms of schizophrenia and has an antidepressant effect, which is also caused by the action of cariprazine on serotonin 5-HT1A receptors, similarly to other drugs used in depression – selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitor (SNRIs) [20]. Due to its action, cariprazine has been used in the treatment of schizophrenia and bipolar disorder, and the latest reports show its potential in supporting the treatment of autism and it may have pro-cognitive effects [2,21,22].

Current Regulatory Approval and Indications of Cariprazine

Cariprazine has been approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia (1.5–6 mg/day) and bipolar I disorder (3–6 mg/day) in adults since 2015, as an adjunctive therapy for treating major depressive disorder since 2022, and for the treatment of schizophrenia in adults in Europe since 2017 [23–25]. In Poland, there is only 1 preparation that contains cariprazine – called Reagila. Cariprazine is available in doses of 1.5 mg, 3 mg; 4.5 mg, and 6 mg [19,26,27]. It is recommended to start with a dose of 1.5 mg, gradually increasing the maximum daily dose to 6 mg, and it is recommended to take it once a day [23]. Cytochrome P400 3A4 is involved in the metabolism of cariprazine; therefore, patients treated with this drug must be informed about contraindications to the use of other drugs that are inhibitors of this enzyme such as diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, verapamil, and voriconazole. Due to metabolism of cariprazine, the dosage should be reduced by half [28]. Cariprazine is metabolized to active metabolites – desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) [29]. Cariprazine’s half-life is 2–4 days, but the half-life of desmethyl cariprazine (DCAR) is 1–2 days, and that of didesmethyl cariprazine (DDCAR) is 1–3 weeks [29–31]. The most common adverse reactions involved akathisia, dyspepsia, vomiting, and somnolence [32]. Due to the partial stimulation of dopamine receptors in the tuberoinfundibular pathways, cariprazine does not significantly affect prolactin levels, comparable to placebo and aripiprazole, which may be important from the point of view of the treatment of diseases in people additionally struggling with hyperprolactinemia [33]. Moreover, cariprazine has relatively low affinity for the histamine H1 receptor, muscarinic M1 receptors, and α1 receptors [26]. Therefore, its use is expected to be associated with a low risk of sedation, metabolic adverse effects, or hypotension.

Schizophrenia

In a double-blind, placebo-controlled, clinical trial, even low doses (1.5–4.5 mg/day vs high dose, 6–12 mg/day cariprazine) were shown to significantly reduce schizophrenia symptoms in acute exacerbation, as demonstrated by the Positive and Negative Syndrome Scale (PANSS). The long-term efficacy and safety of cariprazine used at the doses given was also assessed, and the most common adverse effects were akathisia (14%), insomnia (14%), and weight gain (12%). Nevertheless, elevations in prolactin levels, changes in cardiovascular parameters, or increased sedation associated with long-term cariprazine administration were not observed [6,34]. In a similar study, the most notable benefit was noted with a daily dosage of 4.5 mg of cariprazine, resulting in a substantial decrease in the PANSS total score by −10.4 [24,35]. In another study, researchers Cutler et al showed that even administration of cariprazine up to 9 mg per day was generally safe and well-tolerated in individuals with schizophrenia during an extended treatment duration, without higher rates of adverse effects than at lower doses [24,36].

In multinational and multicenter placebo-controlled study, individuals receiving cariprazine demonstrated a considerably prolonged time to relapse compared to those on placebo. Specifically, relapse occurred in only 24.8% of cariprazine-treated patients, in contrast to 47.5% of those treated with placebo [37,38].

In another study in patients with schizophrenia and schizoaffective disorder, previously-used antipsychotics were replaced with cariprazine according to previous doses and efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) scale. Maximum doses in some patients were 3.0 mg/day, while others were increased to 6.0 and even 9.0 mg/day. Significant improvements in indices were shown when comparing data at admission and discharge: BPRS decreased from 22 to 5, and in the CGI-S moderately-markedly ill patients improved to between normal/borderline ill. Cariprazine has proven to be very effective in reducing not only negative symptoms, but also positive symptoms and cognitive impairment [3].

A significant effect on the reduction of negative symptoms of schizophrenia was demonstrated in a clinical case series. In 2 young patients with predominant negative symptoms, the existing treatment with risperidone (4.5 mg per day) was modified by adding cariprazine initially at a dose of 1.5 mg/day, increasing to 4.5 mg/day, while reducing the dose of risperidone. Follow-up assessment of patients using the PANSS, Global Assessment of Functioning (GAF) and CGI-S scales showed significant improvement: from scores of 57.5 on PANSS, 3.0 on CGI-S, and 74.5 on GAF to a decrease in PANSS of 23.8%, and improvement in CGI-S of 25% and GAF of 29.5%. However, it is important to note the marginal reduction in the positive PANSS subscale score, decreasing from 20 to 16, whereas a notable improvement of 29.8% was observed in the negative subscale [39]. A similar trend was observed in another clinical case series, also with predominantly negative symptoms, where prior treatment with olanzapine, risperidone, or quetiapine was modified by including cariprazine. After 12-week administration of cariprazine at a dose of 6 mg per day, the positive PANSS scale showed relative stability, while the negative subscale showed a 22% reduction. In addition, there was a 15.4% improvement in the mean CGI-S scale score and a 17% increase in the mean GAF scale score. Overall tolerability was considered satisfactory, with no serious adverse events reported [40].

A number of papers point to the benefits that may occur from the combination of cariprazine with other antipsychotic drugs, in particular cariprazine augmentation of clozapine in treatment-resistant schizophrenia [2,41]. A positive therapeutic impact of this drug combination with CGI-I=2 was noted in 75% of patients following 4–12 weeks of treatment. Enhancements were evident in negative symptoms (58.3%), positive symptoms (41.7%), general functioning (50%), affective symptoms (16.7%), and cognitive functions (8.3%) [2]. In another study assessing the benefits and safety of augmenting clozapine with cariprazine, a notable decrease was observed in the median total PANSS score (from 59 to 22.5), median positive PANSS score (from 11.5 to 5.5), and median negative PANSS score (from 15.5 to 3) [42].

The efficacy of cariprazine in treating negative symptoms of schizophrenia is profoundly significant, as these symptoms substantially decrease the quality of life for patients, often hindering their daily functioning [4]. Furthermore, currently used antipsychotic medications demonstrate effectiveness primarily in reducing positive symptoms, with limited efficacy in treating negative symptoms and cognitive impairments. Moreover, most of these medications have not been extensively studied in populations predominantly presenting with negative symptoms [43]. The reduction of negative symptoms can result in notable enhancements in daily functional abilities and overall quality of life.

Bipolar Disorder

The latest clinical studies available in the literature describe the effectiveness of cariprazine in the treatment of depression in the course of bipolar disorder. A multicenter double-blind, placebo-controlled, phase 3 study from 2020 showed effectiveness in reducing depressive symptoms in patients with bipolar depression, which was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impressions Severity (CGI-S) scores, among others. Patients were depressed without psychotic symptoms. The range of doses of cariprazine that patients took were 1.5 mg/day (162 patients) and 3 mg/day (153 patients). At the end of 6 weeks of follow-up, effectiveness in reducing depressive symptoms in patients taking cariprazine was demonstrated in favor of a lower dose – 1.5 mg/day. Follow-up assessment of patients using the MADRS and CGI-S scales showed significant improvement from scores of 31,5 of MADRS to 16.7 and from 4.5 to 3 of CGI-S. There was no significant difference for cariprazine 3.0 mg/day. The adverse events were akathisia, restlessness, nausea, and fatigue [32].

In a similar study, Yatham et al also showed the effectiveness of cariprazine compared to placebo in reducing symptoms. The conclusions at the 6th week of the study were an improvement in the reduction of depression symptoms on the MADRS scale, the least squares mean difference (LSMD) in favor of cariprazine versus placebo was −2.6 for 1.5–3 mg/day, −2.8 for 2.5 mg/day and −2.4 for 3 mg/day. What is more, the study showed that starting dose from 1.5 mg/day and slow titration led to lower rates of some adverse events in the bipolar depression studies versus the mania studies [44].

The effectiveness of cariprazine has also been demonstrated in the treatment of mania in patients with bipolar disorder; a study demonstrated the effectiveness of a dose of 3–6 mg/day and a higher dose of 6–12 mg/day. Patients were assessed according to the Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity of Illness (CGI-S). On the YMRS scale, the effectiveness was −6.1 [−8.4 to −3.8] in week 3 for a dose of 3–6 mg/day and −5.9 [−8.2, −3.6] for a dose of 6–12 mg/day. The results suggest that cariprazine-treated patients improved in global disease severity. Most of the adverse effects were mild or moderate, and more adverse effects were observed in patients taking a higher dose of cariprazine, at 6–12 mg/day. Akathisia was observed in both groups of patients, while nausea, constipation, and tremor also occurred in patients treated with the higher dose [45].

A study that contained results from 3 randomized, double-blind, placebo-controlled, studies also examined the effectiveness of cariprazine in reducing symptoms in patients with bipolar disorder. Of 1383 patients, 808 currently had manic symptoms. The dose of cariprazine that patients received was 1.5 mg/day and 3 mg/day. In patients with manic symptoms, there was a significantly greater reduction in MADRS total score from baseline to week 6 for cariprazine 1.5 and 3 mg/day compared with placebo, but in patients without manic symptoms, the efficacy was greater for 1.5 mg/day than 3 mg/day [46].

Similar results were obtained in a study conducted by Durgam et al in treatment of mania in patients with bipolar disorder. Cariprazine treatment was initiated at a dose of 1.5 mg/day, increased to 3 mg/day on day 2, and then increased in 3-mg steps to a maximum of 12 mg/day. At the end of the study at week 3, efficacy was −6.1 (−8.9 to −3.3) compared to placebo on the YMRS scale and on the CGI scale score −0.6 (−1.0 to −0.3). Additionally, patients were assessed on the MADRS scale, showing that mean baseline MADRS scores were low and decreased during the study, suggesting that cariprazine treatment did not accelerate depressive symptoms [47].

The above studies demonstrate that cariprazine treatment is effective in the treatment of the bipolar I mood spectrum, from mania with or without depressive symptoms to depression with or without manic symptoms. Importantly, cariprazine is well-tolerated by patients. Overall, cariprazine appears to be a promising option for treatment of bipolar disorder, offering efficacy for depressive and manic symptoms while maintaining tolerability. However, individualized treatment plans and careful consideration of dosing strategies are crucial to optimize therapeutic outcomes and minimize adverse effects.

Cariprazine and Pediatric Patients

There are few clinical studies available in the scientific literature on use of cariprazine in treatment of mental disorders in the pediatric population. The study conducted by Riccobene et al showed the effectiveness of cariprazine in pediatric patients with schizophrenia (13–17 years old) or bipolar I disorder (10–17 years old). The improvement was demonstrated on the PANSS and YMRS scales. The dosage of cariprazine was 1.5, 3, or 4.5 mg/day [48].

Another study on pediatric patients investigated the safety, tolerability, pharmacokinetics, and efficacy of cariprazine in children and adolescents with autism spectrum disorder (ASD). The study population consisted of 25 children aged 5–17 years and the dosage of cariprazine was 0.5–3 mg/day. At the end of the study, improvements were observed on various rating scales such as the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), and the Children’s Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), which may suggest there may be benefits in supporting the treatment of some symptoms associated with ASD. In the that study, the most common adverse effect, reported by 8 patients, was weight gain, observed in children aged 5–9 years. Other effects included increased alanine transaminase (ALT) levels and increased appetite and dizziness [49].

In conclusion, while the available studies are limited, the emerging evidence suggests that cariprazine holds promise in the treatment of mental disorders in pediatric patients, particularly in patients with schizophrenia, bipolar I disorder, and autism spectrum disorder. Further research and larger-scale studies are warranted to deepen our understanding of the efficacy, safety, and optimal dosages of cariprazine in the pediatric population.

Cariprazine and Addictions

Dopamine receptors are likely involved in the onset of addictions, making the use of cariprazine in addiction therapy promising, especially in individuals with coexisting mental disorders such as bipolar disorder, as described in several case reports [37,38]. In such individuals, a more severe course of the disease and more frequent occurrence of psychotic symptoms are often observed [50]. There is a case report of reduction in drug cravings in a patient addicted to methamphetamine. Due to the presence of psychotic symptoms in the patient, such as visual and auditory hallucinations, it was decided to initiate treatment initially with olanzapine and later with risperidone, but without success. Therefore, cariprazine was introduced. Improvement in symptom reduction was achieved, and after 16 weeks of treatment, the patient’s results in the negative and positive subscales of the PANSS scale decreased by 61.76% and 69.9%, respectively. During the treatment the patient has remained free of psychotic symptoms and abstinent from methamphetamine [51].

Another patient with methamphetamine-associated psychosis also showed improvement while taking cariprazine. Before treatment with this drug, the patient was treated with a number of other antipsychotic drugs such as olanzapine, fluoxetine, clonidine, clonazepam, buprenorphine, and aripiprazole, but with poor results. Then cariprazine used at a dose of 6 mg/day resulted in a 60% reduction in psychotic symptoms. On the PANSS scale, within 1 month the patient’s score dropped from 73, classified as mildly ill, to 46, classified as normal, showing the promising results of cariprazine in treatment of comorbid addictions. However, due to lack of cooperation with the patient, no further effects were demonstrated [52].

Due to its action, cariprazine may be an important drug in supporting the treatment of addictions to psychoactive substances, not only to methamphetamine. However, due to the small amount of data, it is crucial to conduct further research in this direction.

Future Directions

Psychiatric diseases such as schizophrenia or bipolar disorder, due to the occurrence of various symptoms, worsen the functioning and quality of life of patients. In addition, numerous adverse effects, occasional lack of cooperation in the doctor–patient relationship, the treatment of these psychiatric diseases increasingly requires new solutions, such as new antipsychotic drugs, especially new third-generation drugs. Cariprazine in the treatment of schizophrenia and bipolar disorder has opened new avenues for research and clinical application. Despite its demonstrated efficacy, several areas require further exploration to optimize its use and maximize patient outcomes in adults and the pediatric population. Long-term studies are required to fully understand the safety profile and long-term effectiveness of cariprazine. Although initial findings are promising, extended follow-up is necessary to evaluate the potential for late-onset adverse effects, including tardive dyskinesia and metabolic syndrome, thereby confirming cariprazine as a viable long-term therapeutic option. Comparative studies of cariprazine with both older and newer antipsychotics will be essential. These studies should evaluate not only clinical effectiveness but also patient well-being and adherence to treatment. This comprehensive approach will facilitate the identification of optimal therapeutic strategies. Additionally, combining cariprazine with psychotherapy may provide synergistic benefits, further improving patient outcomes.

Conclusions

In conclusion, Cariprazine, a novel atypical antipsychotic drug, has demonstrated efficacy in the treatment of various psychiatric disorders, including schizophrenia, bipolar disorder, and depression associated with bipolar disorder. Its unique pharmacological profile, characterized by partial agonism at dopamine D2 and D3 receptors, as well as 5HT1A receptors, with a preference for the D3 receptor, sets it apart from other antipsychotics. Cariprazine’s mechanism of action in the limbic system, particularly its partial agonism of D3 receptors, contributes to its positive impact on negative symptoms in schizophrenia and its antidepressant effect. This dual action makes it a promising option for addressing cognitive faculties and negative symptoms in patients with refractory schizophrenia. In the treatment of schizophrenia, cariprazine has shown efficacy in reducing symptoms, with a notable impact on both positive and negative symptoms. Moreover, its relatively low risk of adverse effects such as sedation, metabolic adverse effects, or hypotension makes it a well-tolerated option. The use of cariprazine in bipolar affective disorder has been investigated, showing effectiveness in both depressive and manic phases. The adverse effects observed, such as akathisia, restlessness, nausea, and fatigue, were generally mild or moderate. Additionally, its minimal impact on prolactin levels makes it advantageous in patients with concerns related to hyperprolactinemia. In summary, cariprazine’s unique pharmacological profile, coupled with its demonstrated efficacy and tolerability, positions it as a valuable therapeutic option for a range of psychiatric conditions. Furthermore, the use of cariprazine in pediatric patients is an area of growing interest, with studies indicating its effectiveness in schizophrenia and bipolar I disorder. However, the limited available literature necessitates further exploration to establish its safety and efficacy in the pediatric population. Further research and clinical experience may provide additional insights into its long-term safety and potential applications in various patient populations.

Acknowledgements

Head of the Institution who provided general support: prof. dr hab. Jolanta Masiak.

Conflict of interest: None declared

Publisher’s note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher

Financial support: None declared
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References

1 Marder SR Umbricht D Negative symptoms in schizophrenia: Newly emerging measurements, pathways, and treatments Schizophr Res 2023 258 71 77 37517366
2 Siwek M Chrobak AA Gorostowicz A Cariprazine augmentation of clozapine in schizophrenia – a retrospective chart review Front Pharmacol 2024 14 1321112 38239199
3 Galmes LN Rancans E Successful high dose antipsychotic treatment with cariprazine in patients on the schizophrenia spectrum: Real-world evidence from a Spanish hospital setting Front Psychiatry 2023 14 1112697 36911111
4 Fleischhacker W Galderisi S Laszlovszky I The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors Eur Psychiatry 2019 58 1 9 30738380
5 Chan V Schizophrenia and psychosis: Diagnosis, current research trends, and model treatment approaches with implications for transitional age youth Child Adolesc Psychiatr Clin N Am 2017 26 2 341 66 28314460
6 Edinoff A Ruoff MT Ghaffar YT Cariprazine to treat schizophrenia and bipolar disorder in adults Psychopharmacol Bull 2020 50 4 83 117 33012874
7 Olivola M Bassetti N Parente S Cognitive effects of lurasidone and cariprazine: A mini systematic review Curr Neuropharmacol 2023 21 12 2431 46 37519001
8 Misiak B Bieńkowski P Samochowiec J Cariprazine – a novel antipsychotic drug and its place in the treatment of schizophrenia Psychiatr Pol 2018 52 6 971 81 30659560
9 Tondo L Vázquez GH Baldessarini RJ Depression and mania in bipolar disorder Curr Neuropharmacol 2017 15 3 353 58 28503106
10 Barata BC Affective disorders and sexual function: from neuroscience to clinic Curr Opin Psychiatry 2017 30 6 396 401 28806269
11 Shen YC Treatment of acute bipolar depression Ci Ji Yi Xue Za Zhi 2018 30 3 141 47 30069121
12 Geddes JR Miklowitz DJ Treatment of bipolar disorder Lancet 2013 381 9878 1672 82 23663953
13 Crapanzano C Casolaro I Amendola C Lithium and valproate in bipolar disorder: From international evidence-based guidelines to clinical predictors Clin Psychopharmacol Neurosci 2022 20 3 403 14 35879025
14 Besag FMC Vasey MJ Sharma AN Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: A systematic review Ther Adv Psychopharmacol 2021 11 20451253211045870 34646439
15 Chen CK Yang SY Park SC Clinical use of mood stabilizers beyond treatment for bipolar disorder: The REAP-MS study Asian J Psychiatr 2023 85 103613 37163943
16 Yalin N Young AH Pharmacological treatment of bipolar depression: What are the current and emerging options? Neuropsychiatr Dis Treat 2020 16 1459 72 32606699
17 Rybakowski JK Mood stabilizers of first and second generation Brain Sci 2023 13 5 741 37239213
18 Rybakowski JK Two generations of mood stabilizers Int J Neuropsychopharmacol 2007 10 5 709 11 17982754
19 Mazza M Marano G Traversi G Cariprazine in bipolar depression and mania: State of the art CNS Neurol Disord Drug Targets 2018 17 10 723 27 30152291
20 Fountoulakis KN Ioannou M Tohen M Antidepressant efficacy of cariprazine in bipolar disorder and the role of its pharmacodynamic properties: A hypothesis based on data Eur Neuropsychopharmacol 2023 72 30 39 37060629
21 Nakajima S Gerretsen P Takeuchi H The potential role of dopamine D3 receptor neurotransmission in cognition Eur Neuropsychopharmacol 2013 23 8 799 813 23791072
22 McCreary AC Newman-Tancredi A Serotonin 5-HT1A receptors and antipsychotics – an update in light of new concepts and drugs Curr Pharm Des 2015 21 26 3725 31 26044980
23 McCormack PL Cariprazine: First global approval [published correction appears in Drugs. 2016;76(3):419] Drugs 2015 75 17 2035 43 26510944
24 Tarzian M Ndrio M Kaja S Cariprazine for treating schizophrenia, mania, bipolar depression, and unipolar depression: a review of its efficacy Cureus 2023 15 5 e39309 37378203
25 Earley W Guo H Daniel D Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: A post hoc analysis of pooled data Schizophr Res 2019 204 282 88 30172595
26 Cariprazine hydrochloride for schizophrenia Aust Prescr 2021 44 5 170 71 34728883
27 Summary of Product Characteristics Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/reagila
28 Vasiliu O The pharmacogenetics of the new-generation antipsychotics – a scoping review focused on patients with severe psychiatric disorders Front Psychiatry 2023 14 1124796 36873203
29 Mauri MC Paletta S Di Pace C Clinical pharmacokinetics of atypical antipsychotics: An update [published correction appears in Clin Pharmacokinet. 2019;58(9):1219–20] Clin Pharmacokinet 2018 57 12 1493 528 29915922
30 Citrome L Cariprazine: Chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability Expert Opin Drug Metab Toxicol 2013 9 2 193 206 23320989
31 Patel A Patel A Patel D Mini review on cariprazine: A promising antipsychotic agent CNS Neurol Disord Drug Targets 2023 22 2 226 36 35331126
32 Earley WR Burgess MV Khan B Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study Bipolar Disord 2020 22 4 372 84 31628698
33 Culpepper L Vieta E Kelly DL Minimal effects of cariprazine on prolactin levels in bipolar disorder and schizophrenia Neuropsychiatr Dis Treat 2022 18 995 1011 35591886
34 Tiihonen J Mittendorfer-Rutz E Majak M Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia JAMA Psychiatry 2017 74 7 686 93 28593216
35 Durgam S Starace A Li D An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: A phase II, randomized clinical trial Schizophr Res 2014 152 2–3 450 57 24412468
36 Cutler AJ Durgam S Wang Y Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: Results from a 1-year open-label study CNS Spectr 2018 23 1 39 50 28478771
37 Durgam S Earley W Li R Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial [published correction appears in Schizophr Res. 2018;192: 493] Schizophr Res 2016 176 2–3 264 71 27427558
38 Choi YK Adham N Kiss B Long-term effects of cariprazine exposure on dopamine receptor subtypes CNS Spectr 2014 19 3 268 77 24229617
39 Ivanova E Maslinkova D Polnareva N Case series: Cariprazine in early-onset schizophrenia Front Psychiatry 2023 14 1155518 37124247
40 Vasiliu O Case report: Cariprazine efficacy in young patients diagnosed with schizophrenia with predominantly negative symptoms Front Psychiatry 2021 12 786171 34880797
41 Muscatello MR Bruno A De Fazio P Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine Expert Opin Pharmacother 2014 15 16 2329 45 25284216
42 Pappa S Kalniunas A Sharma H Efficacy and safety of cariprazine augmentation in patients treated with clozapine: A pilot study Ther Adv Psychopharmacol 2022 12 20451253221132087 36439679
43 Summary of Product Characteristics Available from: https://bifold.aotm.gov.pl/assets/files/zleceniamz/2020/004/AW/4%20AW%20OT%204330%201%202020%20Agila%20APD%202020.10.09.pdf
44 Yatham LN Vieta E McIntyre RS Broad efficacy of cariprazine on depressive symptoms in bipolar disorder and the clinical implications Prim Care Companion CNS Disord 2020 22 5 20m02611
45 Calabrese JR Keck PE Jr Starace A Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: A double-blind, placebo-controlled study J Clin Psychiatry 2015 76 3 284 92 25562205
46 McIntyre RS Suppes T Earley W Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: Post hoc analysis of 3 randomized, placebo-controlled studies CNS Spectr 2020 25 4 502 10 31576791
47 Durgam S Starace A Li D The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: A phase II trial Bipolar Disord 2015 17 1 63 75 25056368
48 Riccobene T Riesenberg R Yeung PP Pharmacokinetics, safety, and tolerability of cariprazine in pediatric patients with bipolar I disorder or schizophrenia J Child Adolesc Psychopharmacol 2022 32 8 434 43 36282772
49 Yeung PP Johnson KA Riesenberg R Cariprazine in pediatric patients with autism spectrum disorder: Results of a pharmacokinetic, safety and tolerability study J Child Adolesc Psychopharmacol 2023 33 6 232 42 37437109
50 Salloum IM Thase ME Impact of substance abuse on the course and treatment of bipolar disorder Bipolar Disord 2000 2 3 Pt 2 269 80 11249805
51 Grunze H Csehi R Born C Barabássy Á Reducing addiction in bipolar disorder via hacking the dopaminergic system Front Psychiatry 2021 12 803208 34970175
52 Moran RA Hastings C Della-Pietra U A case report of treatment with cariprazine in a recurrent psychosis presumably induced by methamphetamine Cureus 2023 15 10 e47135 38021522
