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Kaul I, Sawchak S, Claxton A, Sauder C, Hassman HH, Kakar R, Walling DP, Citrome L, Zhu H, Miller AC, Brannan SK. Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:102. [PMID: 39488504 PMCID: PMC11531488 DOI: 10.1038/s41537-024-00525-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 10/09/2024] [Indexed: 11/04/2024]
Abstract
In the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials, xanomeline and trospium chloride (formerly known as KarXT) significantly improved symptoms of schizophrenia and was generally well tolerated. We pooled data from the EMERGENT trials to further characterize the efficacy of xanomeline/trospium and provide sufficient statistical power to analyze responses in participant subgroups. In pooled analyses, xanomeline/trospium significantly improved Positive and Negative Syndrome Scale (PANSS) total score at week 5 versus placebo (least squares mean difference, -9.9; 95% confidence interval, -12.4, -7.3; p < 0.0001; Cohen's d effect size, 0.65). PANSS subscale and Clinical Global Impression-Severity scores also improved significantly with xanomeline/trospium versus placebo. Subgroup analyses consistently favored xanomeline/trospium over placebo regardless of differences in participant age, sex, race, body mass index, and baseline PANSS total score. These results add to existing evidence demonstrating robust and reliable improvements in symptoms with xanomeline/trospium across a broad spectrum of people with schizophrenia.
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Affiliation(s)
- Inder Kaul
- Bristol Myers Squibb, Princeton, NJ, USA
| | | | | | | | | | | | - David P Walling
- CenExel-Collaborative Neuroscience Research, Los Alamitos, CA, USA
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Pantovic-Stefanovic M, Karanovic J, Jurisic V, Dunjic-Kostic B, Nesic M, Dodic S, Gostiljac M, Puric M, Savic Pavicevic D, Ivkovic M. Mood disorders and 5-HTR2A genetic variants - the moderator effect of inflammation on expression of affective polarity phenotype. BMC Psychiatry 2024; 24:747. [PMID: 39472813 PMCID: PMC11520582 DOI: 10.1186/s12888-024-06207-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Although repeatedly confirmed, the molecular nature of gene-environment (GxE) interactions has rarely been investigated in the clinical context of mood disorders. This study assesses the relationship between HTR2A genetic variants and the modulatory effect of inflammation in a collective cohort of patients with major depressive disorder (MDD) and bipolar disorder (BD), as a unified group with two distinct phenotypes. METHODS The study included 138 patients with acute mood episodes (BD = 83; MDD = 55). HTR2A rs6313 and rs6314 genotyping was performed while measuring platelet-derived indicators of inflammation (platelet count (PLT), mean platelet volume (MPV), plateletcrit, and platelet distribution width) and the MPV/PLT ratio. RESULTS The HTR2A rs6313 variant is a significant predictor of the polarity phenotype in mood disorders, with the MPV/PLT ratio moderating this relationship, but only under low-inflammatory conditions. In more pronounced inflammatory states, genetic influences lose their predictive role. CONCLUSIONS To our knowledge, this is the first study to investigate the complex interplay between platelet-derived indicators of inflammation and HTR2A variants in the context of mood disorders. Without pro-inflammatory conditions, mood disorders seem to be more genetically determined. Under pro-inflammatory conditions, phenotypic presentation is less dependent on genetic factors. GxE interactions in mood disorders are multifaceted, context-dependent and relevant for assessing their clinical presentation and course.
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Affiliation(s)
- Maja Pantovic-Stefanovic
- Department for Bipolar Disorders, Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia.
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia.
| | - Jelena Karanovic
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, Belgrade, 11000, Serbia
- Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444A, Belgrade, 11042, Serbia
| | - Vladimir Jurisic
- Faculty of Medical Scinces, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 11000, Serbia
| | - Bojana Dunjic-Kostic
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia
- Institute of Mental Health, Milana Kasanina 3, Belgrade, 11000, Serbia
| | - Milica Nesic
- Department for Bipolar Disorders, Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia
| | - Sara Dodic
- Department for Bipolar Disorders, Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia
| | - Marta Gostiljac
- Department for Bipolar Disorders, Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia
| | - Marija Puric
- Department for Bipolar Disorders, Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia
| | - Dusanka Savic Pavicevic
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, Belgrade, 11000, Serbia
| | - Maja Ivkovic
- Department for Bipolar Disorders, Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia
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Patel A, Patel A, Patel D, Patel K, Bambharoliya T. Mini Review on Cariprazine: A Promising Antipsychotic Agent. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:226-236. [PMID: 35331126 DOI: 10.2174/1871527321666220324121935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 12/14/2021] [Accepted: 01/17/2022] [Indexed: 12/16/2022]
Abstract
Cariprazine is a piperazine derivative approved by the USFDA in 2015 as a novel atypical antipsychotic drug (APD) to treat adults with schizophrenia and bipolar manic or mixed episodes in adults. However, due to the partial agonist action on dopamine D2, D3 receptors, and serotonin 5-HT1A receptors as well as the antagonist effect on 5-HT2A, 5-HT2B, and H1 receptors, cariprazine differs pharmacologically from other APDs, both typical and atypical. Moreover, cariprazine also has a unique pharmacokinetic profile due to the formation of two clinically significant metabolites: desmethyl-cariprazine (DCAR) and desmethyl-cariprazine (DDCAR). They are eliminated by CYP3A4 and also, to a lesser extent, by CYP2D6. Here, we also review the effectiveness, safety, as well as current clinical update of cariprazine in bipolar I disorder associated with/without mania and schizophrenia through randomized and post-hoc analysis. The potential benefits of cariprazine as a promising therapeutic alternative in addressing major clinical requirements for better therapy of such severe neuropsychiatric conditions were demonstrated in this summarized review study.
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Affiliation(s)
- Ashish Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Arya Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Darshini Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Krina Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
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Lobo MC, Whitehurst TS, Kaar SJ, Howes OD. New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics. Neurosci Biobehav Rev 2022; 132:324-361. [PMID: 34838528 PMCID: PMC7616977 DOI: 10.1016/j.neubiorev.2021.11.032] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/13/2021] [Accepted: 11/21/2021] [Indexed: 01/07/2023]
Abstract
Schizophrenia is associated with substantial unmet needs, highlighting the necessity for new treatments. This narrative review compares the pharmacology, clinical trial data and tolerability of novel medications to representative antipsychotics. Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses. Initial studies indicate pimavanserin and roluperidone improve negative symptoms. Ulotaront and xanomeline showed efficacy for positive and negative symptoms of schizophrenia in phase II trials. BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal.
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Affiliation(s)
- Maria C Lobo
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK.
| | - Thomas S Whitehurst
- MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
| | - Stephen J Kaar
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK.
| | - Oliver D Howes
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK; H. Lundbeck UK, Ottiliavej 9, 2500, Valby, Denmark.
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Barman R, Majumder P, Doifode T, Kablinger A. Newer antipsychotics: Brexpiprazole, cariprazine, and lumateperone: A pledge or another unkept promise? World J Psychiatry 2021; 11:1228-1238. [PMID: 35070772 PMCID: PMC8717034 DOI: 10.5498/wjp.v11.i12.1228] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 07/28/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Antipsychotic agents are used for various indications in the treatment of psychiatric disorders. Despite their proven roles in multiple conditions, the treatment-emergent side effects of antipsychotic medications, such as metabolic side effects, are often the limiting factor for their long-term and short-term uses. Moreover, antipsychotic medications are often criticized for being less effective in treating different disabling symptoms such as negative symptoms of schizophrenia. As a result, the search for safer and more efficacious antipsychotic agents is ongoing. Newer antipsychotic agents are gaining attention related to emerging efficacy and tolerability data in treating neuropsychiatric conditions. In this review, we attempt to appraise the scientific data on psychopharmacology, safety profile, and efficacy of the newer additions to the list of second-generation antipsychotics, namely brexpiprazole, cariprazine, and lumateperone. We conducted a selective review utilizing PubMed, clinicaltrials.gov, and Cochrane databases to gather appropriate publications, keeping broad inclusion criteria. There were no restrictions on the age of the study population or the year of publication. We also cross-referenced articles and references to capture all existing studies. Our review of the current literature indicates that all three antipsychotic agents appear to be promising based on their short-term studies, while long-term studies remain limited. There is also a need for a head to head comparison between the newer antipsychotics with the other antipsychotic agents to ascertain if the newer agents are any better than the others.
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Affiliation(s)
- Rajdip Barman
- Department of Psychiatry, Genesis Health System, Davenport, IA 52804, United States
| | | | - Tejaswini Doifode
- Department of Psychiatry and Behavioral Science, Carilion Clinic-Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, United States
| | - Anita Kablinger
- Department of Psychiatry and Behavioral Science, Carilion Clinic-Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, United States
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Abstract
PURPOSE OF REVIEW Over the last ten years, the treatment of psychosis has seen a near explosion of creative development in both novel agents and new delivery modalities. The current review summarizes these developments over the past decade (2011-2020). We performed a systematic review utilizing PubMed and PsychInfo with the aim of identifying all the RCT and related analyses in adults with psychosis (schizophrenia and mania). RECENT FINDINGS We identified 11 significant developments: the introduction of new antipsychotics cariprazine, brexpiprazole, lumateperone, and pimavanserin; introduction of new delivery methods: subcutaneous long-acting risperidone, aripiprazole lauroxil, transdermal asenapine, and inhaled loxapine; and the introduction of new approaches such as olanzapine/samidorphan for olanzapine-associated weight gain, examination of the TAAR1 agonist SEP 363,856 as a test of concept, and the combination of Xanomeline/Trospium, an M1 and M4 muscarinic receptor agonist in conjunction with a peripheral anticholinergic. Last decade has seen a tremendous development in second-generation antipsychotics which provides unprecedented treatment options for clinicians in treating psychosis.
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Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety. Adv Ther 2021; 38:3652-3673. [PMID: 34091867 PMCID: PMC8279990 DOI: 10.1007/s12325-021-01797-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/15/2021] [Indexed: 12/22/2022]
Abstract
Schizophrenia is characterized by positive, negative, cognitive, and affective symptoms. Antipsychotic medications, which work by blocking the dopamine D2 receptor, are the foundation of pharmacotherapy for schizophrenia to control positive symptoms. Cariprazine is a dopamine D3 receptor-preferring D3/D2 partial agonist antipsychotic that is approved for the treatment of schizophrenia (USA and European Union [EU]) and manic and depressive episodes associated with bipolar I disorder (USA). Partial agonist agents have a lower intrinsic activity at receptors than full agonists, so they act as either functional agonists or functional antagonists depending on the surrounding neurotransmitter environment. Beyond efficacy against positive symptoms, the unique D3-preferring partial agonist pharmacology of cariprazine suggests potential advantages against negative symptoms, and cognitive and functional impairment, which are challenging to treat. The efficacy and safety of cariprazine in adult patients with schizophrenia have been demonstrated in four short-term randomized, double-blind, placebo-controlled clinical trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study versus the active comparator risperidone. Additional post hoc investigations have supported efficacy across individual symptoms and domains in schizophrenia, as well as in diverse areas of interest including cognition, functioning, negative symptoms, hostility, and global well-being. This comprehensive review of cariprazine summarizes its pharmacologic profile, clinical trial evidence, and post hoc investigations. Collective evidence suggests that the pharmacology of cariprazine may offer broad-spectrum efficacy advantages for patients with schizophrenia, including effects against difficult-to-treat negative and cognitive symptoms, as well as functional improvements. Cariprazine was generally safe and well tolerated in patients with short- and long-term exposure and no new safety concerns were associated with longer-duration treatment. Trial registration ClinicalTrials.gov identifiers, NCT00404573, NCT00694707, NCT01104766, NCT01104779, NCT01412060, NCT00839852, NCT01104792.
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Mucci F, Della Vecchia A, Baroni S, Marazziti D. Cariprazine as a therapeutic option for schizophrenia: a drug evaluation. Expert Opin Pharmacother 2021; 22:415-426. [PMID: 33126812 DOI: 10.1080/14656566.2020.1845315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Schizophrenia is a very disabling condition that may result in a significant impairment of individual, professional, and social adjustments. Antipsychotics (APs), the first-line treatment for schizophrenia, in many cases modify the course of the disease, by reducing the institutionalization risk, at the price of severe and invalidating side effects. Cariprazine is one of the latest second-generation APs (SGAs) acting as a partial agonist of type 2 and 3 dopamine receptors, which was recently approved for the treatment of adult schizophrenia.Areas covered: The authors provide a critical review and commentary on the currently available data on the effectiveness and tolerability of cariprazine in schizophrenic patients, with a particular focus on its specific target symptoms.Expert opinion: Cariprazine appears significantly effective on both acute and maintenance treatment of schizophrenia, and in improving positive, negative, and cognitive symptoms, slightly more than other SGAs. It shows a good safety and tolerability profile, with akathisia being its most common side effect. Although further independent studies are needed to clarify its precise advantages over other SGAs, cariprazine seems a promising compound not only in schizophrenia, but also in a broad range of psychiatric conditions, including perhaps bipolar and addictive disorders.
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Affiliation(s)
- Federico Mucci
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena Italy
| | - Alessandra Della Vecchia
- Department Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Stefano Baroni
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena Italy
| | - Donatella Marazziti
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena Italy.,Saint Camillus International University of Health and Medical Sciences, Unicamillus University of Rome, Italy
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Poweleit EA, Colestock M, Kantemneni EC, Strawn JR, Patino LR, DelBello MP, Ramsey LB. Cariprazine in Youth with Bipolar and Psychotic Disorders: A Retrospective Chart Review. J Child Adolesc Psychopharmacol 2020; 30:267-272. [PMID: 31825249 DOI: 10.1089/cap.2019.0106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Objective: To examine the potential effectiveness and tolerability of cariprazine in pediatric bipolar and psychotic disorders. Methods: We retrospectively reviewed the electronic health records of patients <21 years of age prescribed cariprazine to treat bipolar and psychotic disorders. Adverse effects, tolerability, therapeutic response (Clinical Global Impression-Improvement [CGI-I]), and severity of illness (Clinical Global Impression-Severity [CGI-S]) were determined through manual chart review. Results: We identified 16 patients aged 6-20 years who were treated with cariprazine (initial dose: 1.5 mg/day, interquartile range [IQR], 1.5-1.5; endpoint dose: 3 mg/day, IQR, 1.5-4.5). No serious adverse events were reported, but the most commonly reported side effect was weight gain (n = 3, 19%). Of the 14 patients for whom baseline and endpoint body mass index (BMI) data were available, neither changes in BMI (p = 0.391; 0.54 kg/m2, IQR, -0.33 to 1.38) nor BMI percentile (p = 0.71; 0.36%, IQR, -0.49 to 3.97) significantly differed between baseline and endpoint. However, patients receiving ≥4.5 mg/day had a significantly greater BMI increases during the course of treatment compared with those receiving ≤3 mg/day (p = 0.034; -1.14 kg/m2, IQR, -3.65 to 0.53 vs. 1.01 kg/m2, IQR, 0.17-4.88). CGI-S scores (p = 0.016; 4.5, IQR, 4-5 vs. 4, IQR, 3-4) significantly differed from baseline to endpoint. The response rate was 44% (n = 7/16), with responders being prescribed higher doses (p = 0.005; 6 mg/day, IQR, 4.875-6 vs. 3 mg/day, IQR, 3-4.125). Conclusions: Cariprazine may be well tolerated and effective for pediatric bipolar and psychotic disorders; however, compared with higher doses, total daily doses ≤3 mg/day appear to be more tolerable. Prospective controlled studies to further evaluate cariprazine in youth are needed.
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Affiliation(s)
- Ethan A Poweleit
- Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Michaela Colestock
- Molecular, Cellular, and Biochemical Pharmacology, Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Eashwar C Kantemneni
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Jeffrey R Strawn
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Luis R Patino
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Melissa P DelBello
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
| | - Laura B Ramsey
- Divisions of Research in Patient Services and Clinical Pharmacology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Citrome L. Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy. Neuropsychiatr Dis Treat 2018; 14:2563-2577. [PMID: 30323605 PMCID: PMC6179724 DOI: 10.2147/ndt.s159704] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cariprazine is an oral antipsychotic approved in the US and EU for the treatment of schizophrenia. Cariprazine differs from other antipsychotics in that it is a dopamine D3- and D2-receptor partial agonist, with tenfold higher affinity for D3 receptors than for D2 receptors. Cariprazine is metabolized in two steps by CYP3A4 to didesmethyl-cariprazine (DDCAR). DDCAR has a long half-life of 1-3 weeks and is the predominant circulating active moiety. Efficacy and safety in persons with acute schizophrenia were assessed in four similarly designed, short-term, randomized, placebo-controlled clinical trials in nonelderly adults, with three studies considered positive and yielding a number needed to treat vs placebo for response (change from baseline ≥30% in Positive and Negative Syndrome Scale total score) of ten for the approved dose range of cariprazine 1.5-6 mg/day. The most common adverse reactions were extrapyramidal symptoms (15% and 19% for 1.5-3 and 4.5-6 mg/day, respectively, vs 8% for placebo) and akathisia (9% and 12.5% for 1.5-3 and 4.5-6 mg/day, respectively, vs 4% for placebo). For the approved dose range, rates of discontinuation because of an adverse event were lower overall for patients receiving cariprazine vs placebo (9% vs 12%). Weight and metabolic profile appear favorable. Cariprazine does not increase prolactin levels or prolong the electrocardiographic QT interval. Cariprazine has also been found to be effective for the maintenance treatment of schizophrenia by delaying time to relapse when compared with placebo (HR 0.45). A 26-week randomized clinical trial evidenced superiority of cariprazine over risperidone for the treatment of predominantly negative symptoms in patients with schizophrenia. Cariprazine is also approved in the US for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and is being studied for the treatment of bipolar I depression and major depressive disorder.
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Affiliation(s)
- Leslie Citrome
- Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA,
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Durgam S, Earley W, Lu K, Németh G, Laszlovszky I, Volk S, Litman RE. Global improvement with cariprazine in the treatment of bipolar I disorder and schizophrenia: A pooled post hoc analysis. Int J Clin Pract 2017; 71:e13037. [PMID: 29119668 PMCID: PMC5765496 DOI: 10.1111/ijcp.13037] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 10/12/2017] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Global rating scale measures are useful for assessing the clinical relevance of patient change. Cariprazine, a dopamine D3 and D2 receptor partial agonist, is FDA-approved for the adult treatment of acute manic/mixed episodes of bipolar I disorder and schizophrenia. Post hoc evaluations of Clinical Global Impressions-Severity (CGI-S) scores from the cariprazine pivotal trials in both indications were conducted. METHODS Data from 3 bipolar mania and 3 schizophrenia trials were pooled by indication (bipolar disorder = 1033; schizophrenia = 1466). Cariprazine- and placebo-treated patients were categorised by baseline CGI-S scores; the proportion of patients who improved from more severe categories at baseline to less severe categories at end-point was evaluated using a logistic regression model. Correlations between Young Mania Rating Scale and Positive and Negative Syndrome Scale total score changes and category shifts were also evaluated. RESULTS In both disease states, more cariprazine- than placebo-treated patients had improved CGI-S scores at end-point; more placebo-treated patients had worse end-point scores. More cariprazine- vs placebo-treated patients shifted from the extremely/severely ill to mildly ill/better category (bipolar disorder = 55% vs 36%, odds ratio [OR] = 2.1; P = .09; schizophrenia = 42% vs 18%, OR = 3.4, P<.01). ORs was statistically significant in favour of cariprazine in shifts from marked and moderate illness to borderline/normal in both indications (P < .05). Correlations between rating scale improvement and category shift were greatest in patients with extreme/severe baseline illness for bipolar disorder (-0.853) and schizophrenia (-0.677). CONCLUSIONS Post hoc analyses showed that more cariprazine- than placebo-treated patients with bipolar mania or schizophrenia had statistically significant and clinically meaningful CGI-S improvement.
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Affiliation(s)
| | | | | | | | | | - Stephen Volk
- Medical DirectorApostle Clinical TrialsLong BeachCAUSA
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