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Masand PS, Clayton AH, Parikh M, Laliberté F, Germain G, Mahendran M, Martinez C, Nabulsi N. Healthcare resource utilization and costs of using cariprazine as the first versus subsequent adjunctive therapy for major depressive disorder. J Med Econ 2025; 28:235-244. [PMID: 39841541 DOI: 10.1080/13696998.2025.2457872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/10/2025] [Accepted: 01/21/2025] [Indexed: 01/24/2025]
Abstract
AIM Inadequate response to antidepressant therapy (ADT) is common in major depressive disorder (MDD); atypical antipsychotic (AA) adjunctive therapy may be effective for these patients. This study aimed to compare healthcare resource utilization (HRU) and costs between patients initiating the AA cariprazine as their first adjunctive therapy vs those initiating cariprazine subsequently. METHODS The Merative MarketScan Commercial Database (January 1, 2015, to June 30, 2021) was used to identify US adults with MDD and ≥1 pharmacy claim for cariprazine adjunctive to ADT in 2018 or after. Rates of mental health (MH)‑related and all‑cause HRU per patient-year (PPY) and mean healthcare costs per-patient-per-year (PPPY) were assessed after patients first initiated adjunctive therapy. HRU and costs were compared between cohorts using rate ratios (RRs) and mean cost differences, respectively, estimated from multivariable regression models. RESULTS Of 838 patients receiving cariprazine, 44.7% initiated cariprazine as their first adjunctive therapy to ADT, and 55.3% initiated it subsequently. Those initiating cariprazine first had significantly lower rates of MH‑related hospitalizations (RR [95% confidence interval] = 0.55 [0.30, 0.90], p = .020) and outpatient (OP) visits (0.67 [0.57, 0.82], p < .001) PPY than those initiating cariprazine subsequently. Moreover, patients initiating cariprazine as their first adjunctive therapy had lower annual total MH‑related healthcare costs (mean cost difference [95% confidence interval] -$2,182 [-$4,206, -$69], p = .040), driven primarily by lower OP visit costs (-$1,511 [-$2,330, -$615], p < .001). Similar trends were observed for all-cause HRU and costs. LIMITATIONS This was a retrospective analysis of secondary data with limited follow-up. Claims were a proxy for cariprazine use. CONCLUSIONS Results from this real‑world study of commercially insured US adults suggest that initiating cariprazine as the first adjunctive therapy rather than a subsequent therapy could help mitigate the considerable economic burden of MDD for appropriate patients.
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Affiliation(s)
- Prakash S Masand
- Academic Medicine Education Institute, Duke‑NUS, Singapore, Singapore
| | - Anita H Clayton
- University of Virginia School of Medicine, Charlottesville, VA, USA
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Garel N, Dols A, Yu J, Cresce CD, Rej S, Sajatovic M. Effect of Cariprazine on Outcomes in Older-aged and Younger-aged Patients with Bipolar I Disorder: A Post-hoc Analysis. Am J Geriatr Psychiatry 2025; 33:372-386. [PMID: 39855966 DOI: 10.1016/j.jagp.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/24/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025]
Abstract
OBJECTIVES To evaluate cariprazine in adults with older- and younger-age bipolar I disorder (OABD-I and YABD-I) and compare treatment effects between them. DESIGN AND SETTING Pooled post-hoc analysis of studies in depressive or acute manic/mixed episodes associated with bipolar I disorder. PARTICIPANTS 475/1383 patients (34.3%) in 3 depression trials and 238/1037 patients (23.0%) in 3 manic/mixed trials were OABD-I. INTERVENTIONS Depression: placebo, cariprazine 1.5 mg/day, 3.0 mg/day, pooled 1.5-3.0 mg/day. Manic/mixed: placebo, cariprazine 3.0-6.0 mg/day, and 9.0-12.0 mg/day. MEASUREMENTS Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression of Severity (CGI-S), and Young Mania Rating Scale (YMRS). RESULTS In bipolar I depression, mean change from baseline in MADRS was significantly greater for the pooled cariprazine group vs. placebo in OABD-I (-13.72 vs. -11.98; p < 0.05) and for each cariprazine group vs. placebo among YABD-I. There was no significant difference in treatment effect between OABD-I and YABD-I for either individual cariprazine group vs. placebo. For mania/mixed states, mean change in YMRS was significantly greater for cariprazine 3.0-6.0 mg/day vs. placebo in OABD-I (-19.04 vs. -12.45; p < 0.001) and for both cariprazine groups in YABD-I (-12.49, -19.66 and -18.05 for placebo, cariprazine 3.0-6.0 mg/day and 9.0-12.0 mg/day, respectively [both p < 0.0001 vs. placebo]). There was no significant difference in treatment effect between OABD-I and YABD-I for cariprazine 3.0-6.0 mg/day vs. placebo; there was a significantly higher treatment effect for cariprazine 9.0-12.0 mg/day vs. placebo in the YABD-I subpopulation vs. OABD-I (4.20; p < 0.05). CONCLUSIONS Cariprazine appears to be effective for both depressive and manic/mixed episodes of bipolar I disorder, regardless of age.
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Affiliation(s)
- Nicolas Garel
- Department of Psychiatry and Addictology (NG), Faculty of Medicine, University of Montreal, Montréal, Québec, Canada; Research Centre (NG), Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec H2 × 0A9, Canada.
| | - Annemieke Dols
- Department of Psychiatry (AD), UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jun Yu
- AbbVie Inc. (JY), Sugar Land, TX
| | | | - Soham Rej
- Department of Psychiatry (SR), Jewish General Hospital/Lady Davis Institute, Montreal, Québec, Canada; Department of Psychiatry (SR), McGill University, Montreal, Québec, Canada
| | - Martha Sajatovic
- University Hospitals Cleveland Medical Center (MS), Cleveland, OH; Case Western Reserve University School of Medicine (MS), Cleveland, OH
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Pe LS, Pe KCS, Panmanee J, Govitrapong P, Yang JL, Mukda S. Plausible therapeutic effects of melatonin and analogs in the dopamine-associated pathophysiology of bipolar disorder. J Psychiatr Res 2025; 182:13-20. [PMID: 39793267 DOI: 10.1016/j.jpsychires.2024.12.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/29/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025]
Abstract
Bipolar disorder (BD) is a significant neuropsychiatric condition characterized by marked psychological mood disturbances. Despite extensive research on the symptomatology of BD, the mechanisms underlying its development and presentation remain unknown. Consequently, potential treatments are limited, and existing medications often cause significant side effects, leading to treatment discontinuation. Dopamine (DA) has been implicated in behavioral regulation, reward systems, and mood, highlighting the importance of the dopaminergic system in BD. Elevated levels of DA and tyrosine hydroxylase are associated with the onset of manic episodes, whereas reduced levels are linked to the depressive phase. Additionally, endogenous melatonin (MEL) levels are considerably lower in patients with BD. When administered as a treatment, exogenous MEL and MEL agonists improve behavioral characteristics and significantly modulate DA-related pathophysiological pathways in BD, with minimal adverse effects achieved through MEL receptor activation. Moreover, MEL and MEL agonists offer neuroprotection by promoting physiological homeostasis during disruption. The aim of this review is to investigate and propose MEL receptors as potential novel therapeutic targets for BD. This review seeks to analyze the role of MEL and its agonists in modulating dopamine-related pathophysiological pathways, improving behavioral outcomes, and providing neuroprotection with minimal side effects.
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Affiliation(s)
- Laurence S Pe
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, 73170, Thailand.
| | - Kristine Cate S Pe
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
| | - Jiraporn Panmanee
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, 73170, Thailand.
| | - Piyarat Govitrapong
- Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Laksi, Bangkok, Thailand.
| | - Jenq-Lin Yang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
| | - Sujira Mukda
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, 73170, Thailand.
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McIntyre RS, Llorca PM, Aronin LC, Yu J, Nguyen HB. Effect of Cariprazine on Anhedonia in Patients with Bipolar I Depression: Post Hoc Analysis of Three Randomized Placebo-Controlled Clinical Trials. Adv Ther 2025; 42:246-260. [PMID: 39520655 PMCID: PMC11782341 DOI: 10.1007/s12325-024-03009-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/25/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Anhedonic symptoms in bipolar I (BP-I) depression are associated with decreased quality of life and impaired functioning. We evaluated the effects of cariprazine in patients with BP-I depression with lower or higher levels of anhedonia at baseline. METHODS Data were pooled from three clinical trials (NCT01396447, NCT02670538, NCT02670551) analyzing the effects of cariprazine 1.5 and 3 mg/day in adults with BP-I depression. During post hoc analysis, patients were stratified by baseline median Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor score into a lower (score < median) or higher (score ≥ median) anhedonia subgroup. Outcomes included change from baseline to week 6 in MADRS total and anhedonia factor score, with the latter also evaluated after adjusting for other depressive symptoms. Between-group differences in change from baseline to week 6 were compared using least-squares mean differences (LSMD) analyzed via a mixed-effect model for repeated measures. RESULTS Median baseline anhedonia factor score was 19, defining the lower (placebo = 211; cariprazine 1.5 mg/day = 200, 3 mg/day = 212) and higher (placebo = 249; cariprazine 1.5 mg/day = 261, 3 mg/day = 250) anhedonia subgroups. In the lower subgroup, cariprazine 1.5 mg/day but not 3 mg/day was superior to placebo in reducing MADRS total (LSMD [95% CI] 1.5 mg/day = - 2.61 [- 4.28, - 0.93], P = .0024) and anhedonia factor scores (- 1.70 [- 2.77, - 0.62], P = .0021) at week 6. In the higher subgroup, both cariprazine doses were associated with significantly greater reductions than placebo in MADRS total (1.5 mg/day = - 3.01 [- 4.84, - 1.19], P = .0012; 3 mg/day = - 3.26 [- 5.12, - 1.40], P = .0006) and anhedonia factor scores (1.5 mg/day = - 1.97 [- 3.13, - 0.81], P = .0009; 3 mg/day = - 2.07 [- 3.26, - 0.89], P = .0006). Anti-anhedonic effects were preserved after adjusting for other depressive symptoms, suggesting the effect was not pseudospecific. Patients in the higher subgroup had higher baseline depression and therefore the lower subgroup may have had a floor effect. CONCLUSION Cariprazine demonstrated antidepressant and specific anti-anhedonic effects regardless of baseline anhedonia symptoms in patients with BP-I depression. TRIAL REGISTRATION ClinicalTrials.gov identifiers, NCT02670538, NCT02670551, NCT01396447.
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Affiliation(s)
| | - Pierre-Michel Llorca
- University of Clermont Auvergne, UMR 6602 Institut Pascal (IP), Clermont-Ferrand, France
| | | | - Jun Yu
- AbbVie, North Chicago, IL, USA
| | - Huy-Binh Nguyen
- AbbVie, North Chicago, IL, USA.
- , 100 Park Avenue, Florham Park, NJ, 07932, USA.
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Vieta E, McIntyre RS, Yu J, Aronin LC, Kramer K, Nguyen HB. Full-spectrum efficacy of cariprazine across manic and depressive symptoms of bipolar I disorder in patients experiencing mood episodes: Post hoc analysis of pooled randomized controlled trial data. J Affect Disord 2024; 366:136-145. [PMID: 39187200 DOI: 10.1016/j.jad.2024.08.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 07/17/2024] [Accepted: 08/23/2024] [Indexed: 08/28/2024]
Abstract
INTRODUCTION Patients with bipolar I disorder may experience mood destabilization or treatment-emergent affective switch (TEAS) from one symptom pole to the other spontaneously or following treatment. Optimal treatment should address symptoms from both poles without precipitating destabilization. METHODS These were pooled post hoc analyses of data from randomized, double-blind, placebo-controlled studies of cariprazine 3-12 mg/d for bipolar I mania (NCT00488618, NCT01058096, NCT01058668) and cariprazine 1.5 mg/d or 3 mg/d for bipolar I depression (NCT01396447, NCT02670538, NCT02670551). Changes from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6 and Young Mania Rating Scale (YMRS) total score at week 3 were analyzed in each indication using a mixed-effects model for repeated measures. Percentages of patients with increasing levels of endpoint response and TEAS (bipolar mania = MADRS total score ≥ 19; bipolar depression = YMRS score ≥ 16) were determined. RESULTS Cariprazine significantly reduced manic and depressive symptoms in patients with bipolar I disorder mood episodes. In patients with a manic episode and up to mild baseline depressive symptoms, cariprazine also significantly reduced depressive symptoms. In patients with a depressive episode and manic symptoms in remission at baseline, numerical reduction (without statistical significance) in YMRS indicated no worsening of mania. In both indications, cariprazine-treated patients had numerically greater response rates (presenting symptom pole) than placebo-treated patients; lower percentages of cariprazine- than placebo-treated patients had TEAS at visits where data were collected. LIMITATIONS Post hoc analysis. CONCLUSION Results suggested that cariprazine had full-spectrum efficacy across symptoms from both poles in patients with bipolar I disorder mood episodes; TEAS risk was low. Patient-level response suggested that improvement was clinically relevant.
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Affiliation(s)
- Eduard Vieta
- Department of Psychiatry and Psychology, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Roger S McIntyre
- Department of Psychiatry and Pharmacology, University of Toronto, Toronto, ON, Canada
| | - Jun Yu
- Data and Statistical Sciences, AbbVie, Florham Park, NJ, United States
| | | | - Ken Kramer
- US Medical Affairs, AbbVie, Florham Park, NJ, United States
| | - Huy-Binh Nguyen
- US Medical Affairs, AbbVie, Florham Park, NJ, United States.
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Tarchi L, Bugini S, Dani C, Cassioli E, Rossi E, Lucarelli S, Ricca V, Caini S, Castellini G. Efficacy of Cariprazine in the Psychosis Spectrum: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials in Schizophrenia and Bipolar Disorder. CNS Drugs 2024; 38:961-971. [PMID: 39382790 PMCID: PMC11543740 DOI: 10.1007/s40263-024-01125-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/03/2024] [Indexed: 10/10/2024]
Abstract
BACKGROUND AND OBJECTIVE Psychosis represents one of the most challenging clinical presentations in psychiatry. Schizophrenia and bipolar disorder may both present psychotic features, and cariprazine may offer improvement in the treatment and care of these conditions. Therefore, the objective of the current work was to synthesise results of efficacy for cariprazine in these disorders. METHODS In total, five electronic databases were searched for randomized controlled trials enrolling patients across the psychosis spectrum, using the search term 'Cariprazine' (PubMed, Embase, clinicaltrials.gov, EUDRACT, Cochrane-last search January 2024). No filter or limits were employed. Effect sizes were extracted, by the mean difference in psychometric variables before and after the intervention (Clinical Global Impression Scale, Positive and Negative Symptom Scale, Montgomery-Asberg Depression Rating Scale, Young Mania Rating Scale, Hamilton Anxiety Rating Scale). RESULTS In total, 12 studies enrolling either patients with schizophrenia or bipolar disorder were included (total n = 6477; n = 4814 patients treated with cariprazine, n = 1663 controls treated with placebo). Cariprazine was effective in reducing global clinical severity, and higher improvements were observed at increasing dosages (- 0.25 at ≤ 1.5 mg/day, - 0.45 at ≥ 3 mg/day). Cariprazine also effectively reduced psychotic total scores: - 6.74, [95% confidence interval (CI) - 8.31; - 5.17], depression: - 1.78, [95% CI - 2.54; - 1.02], mania: - 5.72, [95% CI - 6.95; - 4.49], and anxiety symptoms: - 1.24, [95% CI - 1.92; - 0.56]. CONCLUSIONS Cariprazine was observed as efficacious across retrieved studies, offering a potential for tailored treatments across the psychosis spectrum. REGISTRATION NUMBER https://osf.io/pmyhq .
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Affiliation(s)
- Livio Tarchi
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Susan Bugini
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Cristiano Dani
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Emanuele Cassioli
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Eleonora Rossi
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | | | - Valdo Ricca
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Saverio Caini
- Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention, and Clinical Network (ISPRO), 50139, Florence, Italy
| | - Giovanni Castellini
- Psychiatry Unit, Department of Health Sciences, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
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García-Fernández L, Romero-Ferreiro V, Peñuelas-Calvo I, Álvarez-Mon MA, Scala M, Romero-Ferreiro C, López EJ, Santos JL, Rodriguez-Jimenez R. Cariprazine and Cognition in Patients with Schizophrenia and Bipolar Disorder: A Systematic Review. Harv Rev Psychiatry 2024; 32:207-217. [PMID: 39514868 DOI: 10.1097/hrp.0000000000000411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
BACKGROUND Cariprazine (CAR), an antipsychotic with partial agonism at the D3 receptor and higher affinity than dopamine, has shown significant procognitive effects in preclinical animal studies. This study systematically reviews CAR's effects on cognitive measures in patients with schizophrenia and bipolar disorder. METHODS Two independent reviewers systematically searched PubMed, Web of Science, Scopus, and the Cochrane Library up to May 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Additional studies were found by hand searching the references of included studies. Eligible studies were randomized controlled trials (RCTs) in English that assessed CAR's effects on cognition in patients with schizophrenia or bipolar disorder. Quality was assessed using the Jadad scale. RESULTS Out of 139 reports, 5 studies (involving 6,104 patients with schizophrenia or bipolar disorder) were included. In schizophrenia, CAR showed better cognitive outcomes (mainly indirect measures) than placebo (PBO) in both early and late stages. It also outperformed risperidone and aripiprazole in attention-related cognitive tests. In bipolar disorder, CAR improved cognition compared to PBO (also using indirect measures). Most studies found the greatest cognitive benefits with low doses of CAR (1.5-3 mg/d). CONCLUSIONS CAR improved cognitive measures compared to PBO and other D2 antagonists or partial agonists in RCTs, especially in patients with greater baseline impairment. Thus, CAR may be a promising option for enhancing cognition in schizophrenic and bipolar patients; though, more trials using specific cognitive assessment tools are needed. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42023485028.
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Affiliation(s)
- Lorena García-Fernández
- From Clinical Medicine Department, Universidad Miguel Hernández (Dr. García-Fernández); Psychiatry Department, Hospital Universitario de San Juan, Alicante, Spain (Dr. García-Fernández); CIBERSAM-ISCIII (Biomedical Research Networking Centre for Mental Health), Spain (Drs. García-Fernández, Santos, Rodriguez-Jimenez, and Romero-Ferreiro); European University of Madrid (Dr. Romero-Ferreiro); The Research Institute Hospital 12 de Octubre-Imas12 (Drs. Peñuelas-Calvo, Rodriguez-Jimenez, and Romero-Ferreiro), Madrid, Spain; Complutense University of Madrid-UCM (Drs. Peñuelas-Calvo and Rodriguez-Jimenez); Department of Medicine and Medical Specialities, University of Alcala (Dr. Álvarez-Mon); Department of Psychiatry and Mental Health. Hospital Universitario Infanta Leonor (Dr. Álvarez-Mon); Ramón y Cajal Institute of Sanitary Research-IRYCIS (Dr. Álvarez-Mon), Madrid, Spain; Department of Biomedical and Neuromotor Sciences, University of Bologna (Dr. Scala); Faculty of Health Sciences, Universidad Francisco de Vitoria (Dr. Romero-Ferreiro); CIBERESP/ISCIII (Biomedical Research Networking Centre for Epidemiology and PublicHealth/Carlos III Health Institute), Spain (Dr. Romero-Ferreiro); Center for Social and Health Research, University of Castilla-La Mancha (Dr. Jiménez López); Department of Psychiatry, Virgen de La Luz Hospital (Drs. Jiménez López and Santos); Neurobiological Research Group, Technological Institute, University of Castilla-La Mancha (Dr. Santos), Cuenca, Spain
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Martins-Correia J, Fernandes LA, Kenny R, Salas B, Karmani S, Inskip A, Pearson F, Watson S. Cariprazine in the acute treatment of unipolar and bipolar depression: A systematic review and meta-analysis. J Affect Disord 2024; 362:297-307. [PMID: 38942207 DOI: 10.1016/j.jad.2024.06.099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 06/15/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
BACKGROUND Cariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's efficacy in treating acute major depressive episodes in individuals with major depressive disorder (MDD) or bipolar disorder. METHODS A systematic review was conducted on MEDLINE, Embase, PsycINFO, Scopus and Web of Science, ClinicalTrials.gov and ScanMedicine. Study quality was assessed using the RoB 2 tool. Pairwise and dose-response meta-analyses were conducted with RStudio. Evidence quality was assessed with GRADE. RESULTS Nine RCTs meeting inclusion criteria encompassed 4889 participants. Cariprazine, compared to placebo, significantly reduced the MADRS score (MD = -1.49, 95 % CI: -2.22 to -0.76) and demonstrated significantly higher response (RR = 1.21, 95 % CI: 1.12 to 1.30) and remission (RR = 1.19, 95 % CI: 1.06 to 1.34) rates. Subgroup analysis unveiled statistically significant reductions in MADRS score in MDD (MD = -1.15, 95 % CI: -2.04 to -0.26) and bipolar I disorder (BDI) (MD = -2.53, 95 % CI: -3.61 to -1.45), higher response rates for both MDD (RR = 1.19, 95 % CI: 1.08 to 1.31) and BDI (RR = 1.27, 95 % CI: 1.10 to 1.46), and higher remission rates only for BDI (RR = 1.41, 95 % CI: 1.24 to 1.60). A higher rate of treatment discontinuation due to adverse events was observed. LIMITATIONS Reliance solely on RCTs limits generalisability; strict criteria might not reflect real-world diversity. CONCLUSIONS Cariprazine demonstrates efficacy in treating major depressive episodes, although variations exist between MDD and BDI and tolerability may be an issue.
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Affiliation(s)
- João Martins-Correia
- Department of Public Health and Forensic Sciences, Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal.
| | - Luís Afonso Fernandes
- Department of Psychiatry, Hospital Prof. Doutor Fernando Fonseca, EPE, Amadora, Portugal
| | - Ryan Kenny
- Evidence Synthesis Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK; National Institute for Health Research Innovation Observatory, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Barbara Salas
- Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sneha Karmani
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
| | - Alex Inskip
- National Institute for Health Research Innovation Observatory, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Fiona Pearson
- Evidence Synthesis Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK; National Institute for Health Research Innovation Observatory, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Stuart Watson
- Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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Tohen M, Yu J, Kramer K, Nguyen HB. Early improvement with cariprazine as a predictor of antidepressant, anxiolytic, and antimanic response in bipolar I mania and depression: A pooled post hoc analysis of randomized cariprazine trials. J Affect Disord 2024; 362:194-200. [PMID: 38942209 DOI: 10.1016/j.jad.2024.06.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 06/03/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
BACKGROUND Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and mania studies; therefore, we assessed whether early improvement with cariprazine predicts eventual treatment response. METHODS Post hoc analyses used pooled data from randomized, double-blind, placebo-controlled bipolar I depression (NCT02670538, NCT02670551) and mania (NCT00488618, NCT01058096, NCT01058668) trials. In depression studies (cariprazine 1.5 mg/d, 3 mg/d, or placebo), early improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) total scores (≥25 % improvement at day 15) and subsequent depressive/anxiety symptom response status (≥50 % improvement at week 6) were assessed. In mania studies (cariprazine 3-12 mg/d or placebo), early improvement in Young Mania Rating Scale (YMRS) total scores (≥25 % improvement at day 7) and manic symptom response status (≥50 % improvement at week 3) were assessed. RESULTS Patients with bipolar I depression and early MADRS improvement were approximately 4- to 6-times as likely to achieve MADRS or HAM-A response than those without early improvement; patients with early HAM-A improvement were approximately 3- to 4-times as likely to achieve MADRS or HAM-A response. A subset of patients without early improvement with cariprazine 1.5 mg/d (20 %-31 %) subsequently responded following up-titration. Patients with mania and early YMRS improvement were approximately 5 times more likely to have manic symptom response than those without early improvement. LIMITATIONS Post hoc analysis; relatively short study durations; flexible-dosing (mania studies). CONCLUSIONS Early symptom improvement with cariprazine may inform therapeutic decisions for patients with bipolar I disorder.
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Affiliation(s)
- Mauricio Tohen
- Department of Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Jun Yu
- AbbVie, Florham Park, NJ, USA
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Paulino Ferreira LP, Martins Batista C, Machado Nogueira JC, Silva Aleixo MA. Mania Associated With Cariprazine: A Case Report and a Review of Literature Regarding Bipolar Depression Treatment With Cariprazine. J Clin Psychopharmacol 2024; 44:517-519. [PMID: 39008888 DOI: 10.1097/jcp.0000000000001892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
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11
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Miljević ČD, Vuković PG, Munjiza-Jovanović A. Clinical challenges in the dosing and titration of cariprazine. Front Psychiatry 2024; 15:1427482. [PMID: 39279811 PMCID: PMC11392870 DOI: 10.3389/fpsyt.2024.1427482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 08/08/2024] [Indexed: 09/18/2024] Open
Abstract
The introduction of a new psychopharmaceutical medication instead of the previous one always poses a certain challenge. In the case of antipsychotics (AP), these problems are considerably more complicated and are mainly caused by the question of dose equivalents, but also by the pharmacokinetic properties of the drug. In the case of partial dopamine D2 agonists, an additional issue is the possibility of deterioration when switching from the previous D2 antagonists to these drugs. Cross-titration is therefore generally recommended. Finally, due to the capsule form, it is not possible to increase the dose of cariprazine by less than 1.5 mg during titration. In this paper, we have presented our proposal to replace the most commonly used second-generation APs with the third-generation AP cariprazine. We have taken into account the dose equivalents, the pharmacological forms of the drugs and their pharmacokinetic and pharmacodynamic properties.
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Affiliation(s)
- Čedo D Miljević
- Clinic for Adults, Institute of Mental Health, Belgrade, Serbia
- Department of Psychiatry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Petar G Vuković
- Clinic for Adults, Institute of Mental Health, Belgrade, Serbia
| | - Ana Munjiza-Jovanović
- Department of Psychiatry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Clinic for Children and Adolescents, Institute of Mental Health, Belgrade, Serbia
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12
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McIntyre RS, Davis B, Rodgers J, Rekeda L, Adams J, Yatham LN. Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder. Bipolar Disord 2024; 26:442-453. [PMID: 38609342 DOI: 10.1111/bdi.13421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2024]
Abstract
INTRODUCTION Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.
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Affiliation(s)
| | - Bethany Davis
- Accelerated Enrollment Solutions, Atlanta, Georgia, USA
| | | | | | | | - Lakshmi N Yatham
- Department of Psychiatry, Institute of Mental Health, University of British Columbia, Vancouver, Canada
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13
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Li S, Xu C, Hu S, Lai J. Efficacy and tolerability of FDA-approved atypical antipsychotics for the treatment of bipolar depression: a systematic review and network meta-analysis. Eur Psychiatry 2024; 67:e29. [PMID: 38487836 PMCID: PMC10988162 DOI: 10.1192/j.eurpsy.2024.25] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or ≤ 10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.
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Affiliation(s)
- Shaoli Li
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, China
- Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310009, China
| | - Chenyue Xu
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, China
| | - Shaohua Hu
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, China
- The Key Laboratory of Mental Disorders’ Management, Zhejiang Province, Hangzhou310003, China
- Brain Research Institute, Zhejiang University, Hangzhou310058, China
- Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou310003, China
- The MOE Frontier Science Center for Brain Science & Brain-machine Integration, Zhejiang University, Hangzhou310058, China
| | - Jianbo Lai
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, China
- The Key Laboratory of Mental Disorders’ Management, Zhejiang Province, Hangzhou310003, China
- Brain Research Institute, Zhejiang University, Hangzhou310058, China
- Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou310003, China
- The MOE Frontier Science Center for Brain Science & Brain-machine Integration, Zhejiang University, Hangzhou310058, China
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14
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Jain R, McIntyre RS, Cutler AJ, Earley WR, Nguyen HB, Adams JL, Yatham LN. Efficacy of cariprazine in patients with bipolar depression and higher or lower levels of baseline anxiety: a pooled post hoc analysis. Int Clin Psychopharmacol 2024; 39:82-92. [PMID: 37551609 PMCID: PMC10833186 DOI: 10.1097/yic.0000000000000500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 07/09/2023] [Indexed: 08/09/2023]
Abstract
Post hoc analyses evaluated cariprazine, a dopamine D 3 -preferring D 3 /D 2 receptor partial agonist, in patients with bipolar I depression and high baseline anxiety. Data were pooled from two phase 3, randomized, double-blind, placebo-controlled studies in adults with bipolar I disorder and a major depressive episode (NCT02670538, NCT02670551). Cariprazine 1.5 and 3 mg/d were evaluated in patient subgroups with higher and lower baseline anxiety. In patients with higher baseline anxiety, significant differences for cariprazine 1.5 mg/d versus placebo were observed on change in Montgomery-Åsberg Rating Scale (MADRS) total score, Hamilton Anxiety Rating Scale (HAM-A) total score and subscale scores, and rates of MADRS remission ( P < 0.05 all); nonsignificant numerical improvements were observed for cariprazine 3 mg/d versus placebo. In patients with lower anxiety, differences versus placebo were significant for HAM-A (cariprazine 3 mg/d) and MADRS (cariprazine 1.5 and 3 mg/d) total score changes ( P < 0.05 all). Rates of treatment-emergent mania were low and similar for cariprazine and placebo. Cariprazine 1.5 mg/d had consistent effects on anxiety and depression symptoms in patients with bipolar I depression and higher baseline anxiety; tolerability was favorable. Given few proven treatments for this common comorbidity, these preliminary results are promising.
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Affiliation(s)
- Rakesh Jain
- Department of Psychiatry, Texas Tech University School of Medicine – Permian Basin, Midland, Texas, USA
| | - Roger S. McIntyre
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Andrew J. Cutler
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York
| | | | | | | | - Lakshmi N. Yatham
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
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15
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Cutler AJ, Laliberté F, Germain G, MacKnight SD, Boudreau J, Wade SW, Parikh M. Healthcare resource utilization and costs associated with first versus subsequent use of cariprazine for bipolar I disorder. J Med Econ 2024; 27:1472-1484. [PMID: 39531329 DOI: 10.1080/13696998.2024.2419721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
AIMS To evaluate the healthcare resource utilization (HRU) and costs of patients who initiated cariprazine as their first versus subsequent atypical antipsychotic (AA) following a bipolar I disorder (BP-I) diagnosis. METHODS Adults with a BP-I diagnosis (first claim = index), commercial, Medicare Supplemental, or Medicaid insurance, and ≥1 outpatient cariprazine dispensing were identified from Merative MarketScan database. Cohorts included patients who initiated cariprazine as either their first or subsequent AA after initial BP-I diagnosis. Characteristics were balanced between cohorts using inverse probability of treatment weighting (IPTW). Outcomes evaluated post-index included all-cause and mental health (MH)-related HRU (hospitalizations, emergency department [ED] visits, outpatient visits), total healthcare costs (medical + pharmacy), and treatment patterns. HRU and healthcare costs were reported per patient-year (PPY) and compared between cohorts using rate ratios and 95% CIs estimated using nonparametric bootstrap procedures. Treatment patterns were analyzed descriptively, with standardized differences ≥10% considered important. RESULTS After IPTW, cohorts included 1,409 patients who initiated cariprazine first and 1,621 patients who initiated cariprazine subsequently; the average (standard deviation, SD) observation period was 678 (373) and 758 (389) days for first and subsequent initiators, respectively. Patients who initiated cariprazine first had 23% fewer all-cause hospitalizations and 28% fewer MH-related hospitalizations PPY (each comparison, p < 0.001). Rates of all-cause and MH-related outpatient visits were significantly lower in patients who initiated cariprazine first versus subsequently (each comparison, p < 0.001), while rates of ED visits were similar. Relative to subsequent initiators, first initiators incurred $2,587 and $2,130 lower all-cause and MH-related total healthcare costs PPY, respectively (each comparison, p < 0.05). Before starting cariprazine, first initiators used fewer BP-I-related medications on average than subsequent initiators (2.6 vs 3.9; standardized difference = 23.9%). LIMITATIONS Potential coding inaccuracies and residual confounding. CONCLUSIONS In this real-world database analysis, patients with BP-I who initiated cariprazine as their first AA had lower rates of HRU and incurred lower costs than patients who initiated cariprazine as a subsequent AA.
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Affiliation(s)
- Andrew J Cutler
- Department of Psychiatry, SUNY Upstate Medical University, Lakewood Ranch, FL, USA
| | | | | | | | | | - Sally W Wade
- Wade Outcomes Research and Consulting, Salt Lake City, UT, USA
| | - Mousam Parikh
- Health Economics and Outcomes Research, AbbVie, Florham Park, NJ, USA
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16
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Munayco Maldonado GM, Schwartz TL. Differentiating the third generation of antipsychotics: a focus on lumateperone's similarities and differences. Int Clin Psychopharmacol 2024; 39:4-16. [PMID: 37781859 DOI: 10.1097/yic.0000000000000510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
The development of atypical antipsychotics has evolved to include newer pharmacodynamic properties. Lumateperone, aripiprazole, brexpiprazole, and cariprazine are all dopamine-2 receptor partial agonists with varying receptor affinities. This review aims to compare the clinical and pharmacodynamic differences among these four atypical antipsychotics, all of which are unique when compared to first- and second-generation antipsychotics. For consideration is further delineating these agents as being third-generation antipsychotics. PubMed searches were conducted to compile preclinical and clinical studies derived from animal models and human subjects. Information gathered included pharmacological mechanisms, clinical efficacy, future-oriented clinical approaches, and adverse effects. Efficacy for the shared indications of these drugs seems comparable. Differences among these drugs lie more in their adverse effect profiles. For example, lumateperone was found to have the lowest rate of weight gain while brexpiprazole was found to have the highest rate of weight gain associated with increased appetite. Aripiprazole had the lowest rates of extrapyramidal symptoms not including akathisia while cariprazine had the highest. All four agents reviewed have a variety of receptor affinities, which likely generates a variety of different adverse effects. This suggests that in any given patient, clinicians may see differential clinical effects.
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Affiliation(s)
| | - Thomas L Schwartz
- SUNY Distinguished Teaching Professor and Chair of Psychiatry, Norton College of Medicine at SUNY Upstate Medical University
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17
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Pessina E, Martini A, Raffone F, Martiadis V. Cariprazine augmentation in patients with treatment resistant unipolar depression who failed to respond to previous atypical antipsychotic add-on. A case-series. Front Psychiatry 2023; 14:1299368. [PMID: 38090698 PMCID: PMC10715395 DOI: 10.3389/fpsyt.2023.1299368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 11/07/2023] [Indexed: 10/16/2024] Open
Abstract
Among individuals receiving an adequate pharmacological treatment for Major Depressive Disorder (MDD), only 30% reach a full symptom recovery; the remaining 70% will experience either a pharmacological response without remission or no response at all thus configuring treatment resistant depression (TRD). After an inadequate response to an antidepressant, possible next step options include optimizing the dose of the current antidepressant, switching to a different antidepressant, combining antidepressants, or augmenting with a non-antidepressant medication. Augmentation strategies with the most evidence-based support include atypical antipsychotics (AAs). Few data are available in literature about switching to another antipsychotic when a first augmentation trial has failed. We present a case-series of patients with unipolar treatment resistant depression who were treated with a combination of antidepressant and low dose of cariprazine after failing to respond to a first augmentation with another AA. We report data about ten patients affected by unipolar depression, visited at the outpatients unit of Mental Health Department of ASL CN2 of Bra and NA1 of Napoli (Italy). All patients failed to respond to conventional antidepressant therapy. A low dose of AA (aripiprazole, risperidone or brexpiprazole) was added for one month to the ongoing antidepressant treatment without clinical improvement. A second augmentation trial was then made with cariprazine. Seven out of ten patients were responders at the end of period, of them 1 patient reached responder status by week 2. HAM-D mean scores decreased from 23.9 ± 3.9 (baseline) to 14.8 ± 5.3 (4 weeks). Cariprazine was well tolerated, no severe side effect was observed during the trial. Our sample of treatment resistant unipolar patients showed good response to augmentation with cariprazine. Failure to a first AA-augmentation trial does not preclude response to a second one. This preliminary result requires confirmation through more rigorous studies conducted over greater samples.
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Affiliation(s)
| | | | - Fabiola Raffone
- Department of Mental Health, ASL Napoli 1 Centro, Napoli, Italy
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18
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Leucht S, Dombi ZB, Szabó P, Barabássy Á, Levine SZ. Single trajectory treatment response for predominant negative symptoms: Post-hoc analysis of a clinical trial with cariprazine and risperidone. Schizophr Res 2023; 261:24-30. [PMID: 37688910 DOI: 10.1016/j.schres.2023.09.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023]
Abstract
Examining the heterogeneity of negative symptoms of schizophrenia contributes to the identification of available treatment targets. Generally, prior evidence classified three to four symptom treatment response trajectory groups over the course of positive symptoms, yet, no evidence exists regarding the heterogeneity of medium-term response to predominant negative symptoms. The current post-hoc analysis aims to identify the heterogeneity in negative symptom treatment response trajectories among patients with predominant negative symptoms who received either cariprazine or risperidone for 26 weeks. Treatment response was analyzed based on the: the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and the Clinical Global Impression Severity (CGIS) and Improvement (CGII) scales. To identify subgroups of patients with a similar course of treatment response, group-based trajectory modelling was utilized. Results demonstrated that in comparison with competing models, a single trajectory best described the treatment response of patients with predominant negative symptoms. The results indicate that patients with predominant negative symptoms with over ten years of schizophrenia respond rapidly to adequate treatment and follow a course of steady improvement.
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Affiliation(s)
- Stefan Leucht
- Klinik und Poliklinik für Psychiatrie und Psychotherapie, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | | | - Péter Szabó
- Medical Division, Gedeon Richter Plc., Budapest, Hungary
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Keramatian K, Chithra NK, Yatham LN. The CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence. FOCUS (AMERICAN PSYCHIATRIC PUBLISHING) 2023; 21:344-353. [PMID: 38695002 PMCID: PMC11058959 DOI: 10.1176/appi.focus.20230009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2024]
Abstract
Bipolar disorder is a complex and heterogeneous psychiatric condition that affects more than 2% of the population. The assessment and treatment of bipolar disorder can be a challenge for clinicians, given its clinical complexity and the rapidly changing treatment landscape with the growing range of treatment options that are becoming available for various phases of the illness. To help clinicians navigate the complexity involved in the assessment and management of bipolar disorder, the guidelines of the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) synthesized the evidence on the efficacy, safety, and tolerability of treatments for bipolar disorder and translated it into first-, second-, and third-line treatment recommendations. The main objective of this contribution is to provide clinicians with a summary of the 2018 CANMAT/ISBD guideline recommendations with the addition of any new evidence for the treatment of bipolar disorder across the lifespan.
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Affiliation(s)
- Kamyar Keramatian
- Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nellai K Chithra
- Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lakshmi N Yatham
- Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
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20
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Gill JS. Cariprazine in an Adolescent with Tourette Syndrome with Comorbid Attention Deficit Hyperactive Disorder and Depression: A Case Report. Healthcare (Basel) 2023; 11:2531. [PMID: 37761728 PMCID: PMC10530423 DOI: 10.3390/healthcare11182531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Tourette syndrome is a complex neuropsychiatric condition that manifests in childhood and is often associated with other psychiatric comorbidities. This case report describes a young male with Tourette syndrome with major depressive disorder and attention deficit hyperactivity disorder (ADHD) who experienced troublesome side effects due to his existing medications (escitalopram, risperidone, and methylphenidate). In order to control his tics, ameliorate depressive symptoms, and eliminate side effects of stiffness and sedation, risperidone was switched to cariprazine, a third-generation antipsychotic medication with D3-D2 partial agonism. In addition, the antidepressant dose was also increased. With the new combination, the patient reported good control of his tics, together with significant improvement in depressive symptoms and no side effects. Based on this case and the reviewed literature, cariprazine might be a viable option for patients with Tourette syndrome with other comorbid illnesses who are prone to side effects of medication.
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Affiliation(s)
- Jesjeet Singh Gill
- Department of Psychological Medicine, University Malaya, Kuala Lumpur 50603, Malaysia
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21
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Yeung PP, Johnson KA, Riesenberg R, Orejudos A, Riccobene T, Kalluri HV, Malik PR, Varughese S, Findling RL. Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study. J Child Adolesc Psychopharmacol 2023; 33:232-242. [PMID: 37437109 PMCID: PMC10458368 DOI: 10.1089/cap.2022.0097] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Abstract
Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.
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Affiliation(s)
- Paul P. Yeung
- Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA
| | | | | | - Amelia Orejudos
- Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA
| | - Todd Riccobene
- Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA
| | - Hari V. Kalluri
- Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA
| | - Paul R. Malik
- Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA
| | - Shane Varughese
- Clinical Development Neuroscience, AbbVie Inc., Madison, New Jersey, USA
| | - Robert L. Findling
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
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22
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Côrte-Real B, Saraiva R, Cordeiro CR, Frey BN, Kapczinski F, de Azevedo Cardoso T. Atypical antipsychotic-induced mania: A systematic review and meta-analysis. J Affect Disord 2023; 333:420-435. [PMID: 37084970 DOI: 10.1016/j.jad.2023.04.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 03/26/2023] [Accepted: 04/14/2023] [Indexed: 04/23/2023]
Abstract
BACKGROUND The possibility of atypical antipsychotics (AA) to induce manic symptoms has been raised by several articles. The objective of this study was to describe whether exposure to AA may induce mania in mood disorders. METHODS We performed a systematic review following the preferred reporting items for systematic reviews and meta-analysis guidelines. The systematic search encompassed all relevant studies published until April 4th, 2022. A meta-analysis testing whether treatment emergent mania (TEM) is more frequent with the use of AA compared with placebo was performed. RESULTS A total of 52 studies were included in the systematic review. We found 24 case reports or case series describing 40 manic/hypomanic episodes allegedly induced by AA. Twenty-one placebo-controlled trials were included in a meta-analysis including 4823 individuals treated with AA and 3252 individuals receiving placebo. Our meta-analysis showed that the use of AA protects against the development of TEM (OR: 0.68 [95 % CI: 0.52-0.89], p = 0.005). LIMITATIONS AA-induced mania/hypomania was not the primary outcome in any of the observational or interventional studies. TEM was not homogeneously defined across studies. In most case reports it was not possible to establish causality between the use of AA and the development of manic symptoms. CONCLUSIONS TEM is more frequent with placebo than with AA, which suggests that AA exposure does not represent a relevant risk for TEM. Mania/hypomania induced by an AA seems to be rare events, since anecdotal evidence from case reports and case series were not observed in observational prospective and interventional studies.
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Affiliation(s)
- Beatriz Côrte-Real
- Department of Psychiatry and Mental Health, Centro Hospitalar Universitário Lisboa Norte, Av Prof. Egas Moniz, 1649-035 Lisboa, Portugal; Psychiatric and Medical Psychology University Clinic, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Rodrigo Saraiva
- Department of Psychiatry and Mental Health, Centro Hospitalar Universitário Lisboa Norte, Av Prof. Egas Moniz, 1649-035 Lisboa, Portugal; Psychiatric and Medical Psychology University Clinic, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Catarina Rodrigues Cordeiro
- Department of Psychiatry and Mental Health, Centro Hospitalar Universitário Lisboa Norte, Av Prof. Egas Moniz, 1649-035 Lisboa, Portugal; Psychiatric and Medical Psychology University Clinic, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Benicio N Frey
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada; Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, Hamilton, ON L8N 3K7, Canada
| | - Flavio Kapczinski
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada; Graduate Program in Psychiatry, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, Brazil
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Rakofsky JJ, Lucido MJ, Dunlop BW. All studies are not created equal: A systematic narrative review of bipolar depression clinical trial inclusion/exclusion rules and baseline severity scores. J Affect Disord 2023; 333:130-139. [PMID: 37080495 DOI: 10.1016/j.jad.2023.04.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/26/2023] [Accepted: 04/14/2023] [Indexed: 04/22/2023]
Abstract
BACKGROUND Several bipolar depression treatment guidelines have been designed to assist clinicians with medication selection. When ranking medications, none explicitly considered the inclusion/exclusion criteria or baseline severity scores of the reviewed clinical trials. This article aimed to determine if sufficient differences exist in these variables to justify their consideration when designing treatment guidelines. METHODS Using Ovid and PubMed databases in May and September 2022, all published, short-term cross-over or parallel-group design studies comparing second generation antipsychotics (SGAs), mood stabilizers, or antidepressants versus placebo in bipolar depressed patients were identified. Included studies must have enrolled adult bipolar I/II depressed patients, randomized patients into two or more treatment groups, utilized a double-blind, prospective design written in English, and had primary outcome results that were statistically significant in favor of the investigational treatment. RESULTS Thirty studies met eligibility criteria, comprising a total of 8791 patients. Among those studies, there were seventeen antipsychotic trials, six lithium trials, one lamotrigine trial, three valproate trials, two carbamazepine trials, and two antidepressant trials. The analysis revealed substantial differences among the studies. Although this was seen among all the different drug classes, these differences are clearest when comparing the lithium trials to those of the SGAs. LIMITATIONS Limitations included the selection of severity scores from the treatment arm with the most severe score and the exclusive focus on mood stabilizers, antidepressants, and SGAs. CONCLUSIONS Severity of the enrolled patient sample and treatment-resistance should be considered in addition to other factors when ranking medications in bipolar depression treatment guidelines.
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Fountoulakis KN, Ioannou M, Tohen M, Haarman BCM, Zarate CA. 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. [PMID: 37060629 DOI: 10.1016/j.euroneuro.2023.03.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 03/19/2023] [Accepted: 03/20/2023] [Indexed: 04/17/2023]
Abstract
The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of cariprazine fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of cariprazine. The original model suggests that a constellation of effects on different receptors is necessary and that serotonin reuptake inhibition does not appear to play a significant role in acute bipolar depression. On the contrary, norepinephrine activity seems to be necessary. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition appears essential to sustain it. Overall, the properties of cariprazine fit well the proposed model and add to its validity. A point that needs further clarification is norepinephrine reuptake inhibition which is not yet fully studied for cariprazine.
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Affiliation(s)
- Konstantinos N Fountoulakis
- Professor and Director, 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Greece.
| | - Magdalini Ioannou
- Ph.D. Student, Department of Psychiatry, University Medical Center Groningen, University of Groningen, the Netherlands.
| | - Mauricio Tohen
- University Distinguished Professor and Chairman, Department of Psychiatry and Behavioral Sciences, University of New Mexico Health Sciences Center, 2400 Tucker Ave NE MSC09 5030, Albuquerque, NM 87131-0001, USA.
| | - Bartholomeus C M Haarman
- University of Groningen, University Medical Centre Groningen, Department of Psychiatry, Groningen, the Netherlands.
| | - Carlos A Zarate
- Chief Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892, US.
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25
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Tarzian M, Ndrio M, Kaja S, Beason E, Fakoya AO. Cariprazine for Treating Schizophrenia, Mania, Bipolar Depression, and Unipolar Depression: A Review of Its Efficacy. Cureus 2023; 15:e39309. [PMID: 37378203 PMCID: PMC10292137 DOI: 10.7759/cureus.39309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2023] [Indexed: 06/29/2023] Open
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.
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Affiliation(s)
- Martin Tarzian
- Psychiatry, University of Medicine and Health Sciences, Basseterre, KNA
| | - Mariana Ndrio
- Psychiatry and Behavioral Sciences, University of Medicine and Health Sciences, Basseterre, KNA
| | - Srujan Kaja
- Psychiatry, Larkin Community Hospital, Miami, USA
| | - Elisabeth Beason
- Cardiology, University of Medicine and Health Sciences, Basseterre, KNA
| | - Adegbenro O Fakoya
- Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, USA
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26
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Cai L, Chen G, Yang H, Bai Y. Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review. Int Clin Psychopharmacol 2023:00004850-990000000-00058. [PMID: 36947416 DOI: 10.1097/yic.0000000000000449] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.
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Affiliation(s)
| | - Guanjie Chen
- Teaching Management Office, Shenzhen Mental Health Center, Shenzhen Kangning Hospital, Shenzhen, Guangdong, China
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27
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Sachs GS, Yeung PP, Rekeda L, Khan A, Adams JL, Fava M. Adjunctive Cariprazine for the Treatment of Patients With Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study. Am J Psychiatry 2023; 180:241-251. [PMID: 36789515 DOI: 10.1176/appi.ajp.20220504] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive therapy for patients with major depressive disorder and nonresponse to at least one antidepressant monotherapy. METHODS In this double-blind placebo-controlled study, adults with major depressive disorder and inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day. The primary outcome was change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Least-squares mean differences were estimated in the modified intent-to-treat (mITT) population using a mixed-effects model for repeated measures with adjustment for multiple comparisons. RESULTS The mITT population comprised 751 patients (placebo: N=249; cariprazine 1.5 mg/day: N=250; cariprazine 3.0 mg/day: N=252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (-14.1 vs. -11.5) but not with cariprazine 3.0 mg/day (-13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea. CONCLUSIONS Adjunctive cariprazine at 1.5 mg/day demonstrated efficacy in reducing depressive symptoms in adults with major depressive disorder and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous findings.
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Affiliation(s)
- Gary S Sachs
- Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Sachs, Fava); Signant Health, Blue Bell, Penn. (Sachs); AbbVie, Madison, N.J. (Yeung, Rekeda, Adams); Northwest Clinical Research Center, Bellevue, Wash. (Khan)
| | - Paul P Yeung
- Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Sachs, Fava); Signant Health, Blue Bell, Penn. (Sachs); AbbVie, Madison, N.J. (Yeung, Rekeda, Adams); Northwest Clinical Research Center, Bellevue, Wash. (Khan)
| | - Ludmyla Rekeda
- Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Sachs, Fava); Signant Health, Blue Bell, Penn. (Sachs); AbbVie, Madison, N.J. (Yeung, Rekeda, Adams); Northwest Clinical Research Center, Bellevue, Wash. (Khan)
| | - Arifulla Khan
- Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Sachs, Fava); Signant Health, Blue Bell, Penn. (Sachs); AbbVie, Madison, N.J. (Yeung, Rekeda, Adams); Northwest Clinical Research Center, Bellevue, Wash. (Khan)
| | - Julie L Adams
- Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Sachs, Fava); Signant Health, Blue Bell, Penn. (Sachs); AbbVie, Madison, N.J. (Yeung, Rekeda, Adams); Northwest Clinical Research Center, Bellevue, Wash. (Khan)
| | - Maurizio Fava
- Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Sachs, Fava); Signant Health, Blue Bell, Penn. (Sachs); AbbVie, Madison, N.J. (Yeung, Rekeda, Adams); Northwest Clinical Research Center, Bellevue, Wash. (Khan)
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28
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Gogarnoiu ES, Vogt CD, Sanchez J, Bonifazi A, Saab E, Shaik AB, Soler-Cedeño O, Bi GH, Klein B, Xi ZX, Lane JR, Newman AH. Dopamine D 3/D 2 Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders. J Med Chem 2023; 66:1809-1834. [PMID: 36661568 PMCID: PMC11100975 DOI: 10.1021/acs.jmedchem.2c01624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.
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Affiliation(s)
- Emma S. Gogarnoiu
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Caleb D. Vogt
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Julie Sanchez
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom
- Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, United Kingdom
| | - Alessandro Bonifazi
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Elizabeth Saab
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Anver Basha Shaik
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Omar Soler-Cedeño
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Guo-Hua Bi
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Benjamin Klein
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - Zheng-Xiong Xi
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
| | - J. Robert Lane
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom
- Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, United Kingdom
| | - Amy Hauck Newman
- Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
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29
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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. [PMID: 36911111 PMCID: PMC9998536 DOI: 10.3389/fpsyt.2023.1112697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/01/2023] [Indexed: 03/14/2023] Open
Abstract
Real-world evidence fills in an important gap by providing data on the effectiveness and tolerability of new medications in everyday patients. In this data collection form a Spanish hospital, the effectiveness and tolerability of cariprazine were evaluated in 14 patients who were admitted to the hospital due to an acute episode of schizophrenia or schizoaffective disorder. The collected data included demographic characteristics, history of disorder and previous treatment, and details of cariprazine therapy such as dosing, side effects and measurements of effectiveness via scales. Difference between admission and discharge on the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) scale scores were evaluated using the Wilcoxon Signed-Rank test. Significant improvement was detected in nearly all patients (one patient dropped out) as measured by the BPRS Total, Negative symptom, Positive symptom, and Hostility scores. At admission, patients were markedly-moderately ill and at discharge the severity was reduced to borderline ill and normal according to the CGI-S. The CGI-Improvement scale also indicated very much and much improvement at discharge. Importantly, patients left the hospital with high doses of cariprazine, i.e., 7.5 mg/day or even 9.0 mg/day, but this did not cause safety problems; cariprazine well-tolerated as only a few patients experienced side effects such as akathisia. The results provide novel evidence regarding the tolerability and effectiveness of cariprazine in high doses patients on the schizophrenia spectrum.
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Affiliation(s)
| | - Elmars Rancans
- Department of Psychiatry and Addiction Disorders, Riga Stradins University, Riga, Latvia
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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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Riccobene T, Riesenberg R, Yeung PP, Earley WR, Hankinson AL. Pharmacokinetics, Safety, and Tolerability of Cariprazine in Pediatric Patients with Bipolar I Disorder or Schizophrenia. J Child Adolesc Psychopharmacol 2022; 32:434-443. [PMID: 36282772 DOI: 10.1089/cap.2021.0139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
Abstract
Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This sequential-cohort, dose-escalation study was the first to evaluate the pharmacokinetic, safety, and tolerability profile of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), in pediatric patients with schizophrenia or bipolar I disorder. Methods: This phase I open-label study enrolled patients with schizophrenia (13-17 years of age) or bipolar I disorder (10-17 years of age). Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia or bipolar I disorder and had Positive and Negative Syndrome Scale (PANSS) total scores ≥70 or Young Mania Rating Scale (YMRS) total scores ≥20. Patients were assigned to one of four treatment groups to receive 6 weeks of cariprazine treatment through slow titration to 1.5, 3, or 4.5 mg/d or fast titration to 4.5 mg/d. Pharmacokinetics, adverse events (AEs), and various safety parameters were analyzed. Efficacy was evaluated as an exploratory outcome. Results: A total of 50 participants were enrolled. Based on mean trough levels, steady state appeared to be reached within 1-2 weeks for cariprazine and DCAR and within 4-5 weeks for DDCAR. Systemic exposure of cariprazine, DCAR, and DDCAR generally increased approximately in proportion to the increases in dose from 1.5 to 4.5 mg/d. The most frequent treatment-related, treatment-emergent AEs included sedation, parkinsonism, tremor, dystonia, and blurred vision. Improvements from baseline on the PANSS and YMRS were observed throughout treatment. Conclusion: In this first investigation of cariprazine in a pediatric population with schizophrenia or bipolar disorder, pharmacokinetic parameters were consistent with those observed in adults. Cariprazine appeared to be safe and tolerable in children and adolescents.
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Abstract
OBJECTIVE Cariprazine is the third partial dopamine agonist now available in Australia. This paper will review the properties, evidence and likely clinical place of cariprazine. CONCLUSION Cariprazine is a partial agonist with high affinity at dopamine D2 and D3 receptors, partial agonism at 5HT1a receptors, moderate 5HT2a and H1 antagonism and no anticholinergic activity. It is rapidly absorbed, is unaffected by food, achieves a peak plasma level in 4-8 hours and has high bioavailability. The half-life of cariprazine and its metabolites is long (7-8 days); steady state occurs in 4-8 weeks. It is hepatically metabolized via 3A4 cytochrome enzymes. Cariprazine is an effective antipsychotic in acute schizophrenia in both short and longer placebo-controlled studies. Cariprazine appears to have small advantages in negative symptoms of schizophrenia. While not approved for bipolar disorder, cariprazine is effective in mania and mixed states but requires doses higher than current maximums recommended. Cariprazine causes more akathisia than aripiprazole or brexpiprazole but is less prone to insomnia, weight gain and sedation. Risks for hyperprolactinaemia and QTc prolongation are low. Cariprazine is another 'metabolically-friendly' antipsychotic for schizophrenia, with advantages for those with negative symptoms, mood symptoms or problems with adherence.
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Affiliation(s)
- Judy Hope
- Eastern Health Clinical School, Monash University, Ringgold: 189095903Eastern Health Mental Health Program and Centre for Mental Health Education and Research at Delmont Private Hospital, Melbourne, VIC, Australia
| | - Nicholas A Keks
- Monash Medical Centre and Centre for Mental Health Education and Research at Delmont Private Hospital, 2541Monash University, Melbourne, VIC, Australia
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33
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Serafini G, Nasrallah HA, Amore M. The use of modern dopamine partial agonists in bipolar depression: is the evidence sound? Curr Med Res Opin 2022; 38:773-775. [PMID: 35361016 DOI: 10.1080/03007995.2022.2059973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Gianluca Serafini
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health DINOGMI, Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Mario Amore
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health DINOGMI, Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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34
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Wilke SA, Lavi K, Byeon S, Donohue KC, Sohal VS. Convergence of Clinically Relevant Manipulations on Dopamine-Regulated Prefrontal Activity Underlying Stress Coping Responses. Biol Psychiatry 2022; 91:810-820. [PMID: 35090617 PMCID: PMC11182612 DOI: 10.1016/j.biopsych.2021.11.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Depression is pleiotropic and influenced by diverse genetic, environmental, and pharmacological factors. Identifying patterns of circuit activity on which many of these factors converge would be important, because studying these patterns could reveal underlying pathophysiological processes and/or novel therapies. Depression is commonly assumed to involve changes within prefrontal circuits, and dopamine D2 receptor (D2R) agonists are increasingly used as adjunctive antidepressants. Nevertheless, how D2Rs influence disease-relevant patterns of prefrontal circuit activity remains unknown. METHODS We used brain slice calcium imaging to measure how patterns of prefrontal activity are modulated by D2Rs, antidepressants, and manipulations that increase depression susceptibility. To validate the idea that prefrontal D2Rs might contribute to antidepressant responses, we used optogenetic and genetic manipulations to test how dopamine, D2Rs, and D2R+ neurons contribute to stress-coping behavior. RESULTS Patterns of positively correlated activity in prefrontal microcircuits are specifically enhanced by D2R stimulation as well as by two mechanistically distinct antidepressants, ketamine and fluoxetine. Conversely, this D2R-driven effect was disrupted in two etiologically distinct depression models, a genetic susceptibility model and mice that are susceptible to chronic social defeat. Phasic stimulation of dopaminergic afferents to the prefrontal cortex and closed-loop stimulation of D2R+ neurons increased effortful responses to tail suspension stress, whereas prefrontal D2R deletion reduced the duration of individual struggling episodes. CONCLUSIONS Correlated prefrontal microcircuit activity represents a point of convergence for multiple depression-related manipulations. Prefrontal D2Rs enhance this activity. Through this mechanism, prefrontal D2Rs may promote network states associated with antidepressant actions and effortful responses to stress.
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Affiliation(s)
- Scott A Wilke
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Department of Psychiatry and Behavior Sciences, University of California, San Francisco, San Francisco, California; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California
| | - Karen Lavi
- Department of Psychiatry and Behavior Sciences, University of California, San Francisco, San Francisco, California; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California
| | - Sujin Byeon
- Department of Psychiatry and Behavior Sciences, University of California, San Francisco, San Francisco, California; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California
| | - Kevin C Donohue
- Department of Psychiatry and Behavior Sciences, University of California, San Francisco, San Francisco, California; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California
| | - Vikaas S Sohal
- Department of Psychiatry and Behavior Sciences, University of California, San Francisco, San Francisco, California; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California.
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Hu Y, Zhang H, Wang H, Wang C, Kung S, Li C. Adjunctive antidepressants for the acute treatment of bipolar depression: A systematic review and meta-analysis. Psychiatry Res 2022; 311:114468. [PMID: 35248807 DOI: 10.1016/j.psychres.2022.114468] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 02/15/2022] [Accepted: 02/19/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND The depressive phase of bipolar disorder causes significant functional impairment and disease burden. The efficacy and safety of antidepressants in the treatment of bipolar depression has long been a subject of debate. AIMS To synthesize evidence of the effectiveness, risk of mood switching, and tolerability of adjunctive antidepressants in acute bipolar depression compared to using mood stabilizers or antipsychotics alone. METHOD Multiple databases were searched for randomized controlled trials, including open label and double-blinded, for patients ages 18 or older with acute bipolar depression, comparing efficacy and adverse events in those who used adjunctive antidepressants versus without. Risk of bias and outcomes were assessed using the Cochrane Risk of Bias Tool. This study has PROSPERO registration CRD42016037701. RESULTS Nineteen studies met inclusion criteria. Adjunctive antidepressants showed no significant effect on improving response rate (RR=1.10, 95%CI: 0.98-1.23). Subgroup analysis showed that adjunctive antidepressants with antipsychotics had a small but significantly better response rate compared to antipsychotics alone, which was not seen with adjunctive antidepressants with mood stabilizers. However, that finding was limited by studies predominantly using olanzapine as the antipsychotic medication. Adjunctive antidepressants had no clinically significant impact (but a small statistically significant impact) on improving depressive symptoms (SMD=-0.13, 95%CI: -0.24 to -0.02). There was no association with increased mood switch (RR=0.97, 95%CI: 0.68-1.39) and there was an association with lower dropout due to inefficacy (RR=0.66, 95%CI: 0.45∼0.98). CONCLUSIONS There is no evidence of adjunctive antidepressants clinically improving response rate or depressive symptoms for acute bipolar depression. They are well tolerated, without increasing the risk of short-term mood switch.
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Affiliation(s)
- Yuliang Hu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota, USA
| | - Huijuan Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongyan Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chris Wang
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota, USA
| | - Simon Kung
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota, USA
| | - Chunbo Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China; CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, China; Institute of Psychology and Behavioral Science, Shanghai Jiao Tong University, Shanghai, China.
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Csehi R, Dombi ZB, Sebe B, Molnár MJ. Real-Life Clinical Experience With Cariprazine: A Systematic Review of Case Studies. Front Psychiatry 2022; 13:827744. [PMID: 35370825 PMCID: PMC8970284 DOI: 10.3389/fpsyt.2022.827744] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/15/2022] [Indexed: 11/24/2022] Open
Abstract
Background The hierarchy of evidence coming from evidence-based medicine favors meta-analyses and randomized controlled trials over observational studies and clinical cases. Nonetheless, in the field of psychiatry, where conditions are much more complex, additional evidence coming from real-world clinical practice is necessary to complement data from these gold standards. Thus, in this systematic review, the aim is to summarize the evidence coming from clinical case reports regarding cariprazine, a third-generation antipsychotic drug that has been approved for the treatment of schizophrenia and bipolar I disorder with manic, depressive or mixed features in adults. Methods A systematic review was performed using Embase and Pubmed databases searching for English-language cases published in peer-reviewed journals between 2000 January and 2021 September with the following search terms: (cariprazin* OR "rgh-188" OR rgh188 OR vraylar OR reagila) AND ("case report*" OR "case report"/de OR "case stud*" OR "case study"/de OR "case seri*"). Results After the removal of duplicates, 49 articles were retrieved via the search, from which 22 were suitable for this review. These 22 articles encompassed 38 cases from which 71% described patients with schizophrenia, 16% patients with psychotic disorders, 5% patients with mood disorder and 8% described patients with other disorders such as Wernicke-Korsakoff syndrome, borderline personality disorder and obsessive-compulsive disorder with paranoid schizophrenia. The median age of patients was 31, and half of them were female. The majority of patients (76%) started cariprazine with 1.5 mg/day, and the most common maintenance dose was 4.5 mg/day (34%) and 3.0 mg/day (29%). Conclusion Cariprazine was found to be safe and effective in a wide range of psychiatric conditions with different symptom profiles from acute psychotic symptoms through addiction to negative and cognitive symptoms. The results are in-line with the established evidence from clinical trials, however, they also show how cariprazine can be successfully utilized for treating certain symptoms irrespective of the indication.
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Affiliation(s)
- Réka Csehi
- Global Medical Division, Gedeon Richter Plc, Budapest, Hungary
| | - Zsófia Borbála Dombi
- Global Medical Division, Gedeon Richter Plc, Budapest, Hungary
- Department of Psychiatry, University of Oxford, Oxford, United Kingdom
| | - Barbara Sebe
- Global Medical Division, Gedeon Richter Plc, Budapest, Hungary
| | - Mária Judit Molnár
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary
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The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia. CNS Spectr 2022; 28:319-330. [PMID: 35193729 DOI: 10.1017/s109285292200013x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia. METHODS Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance. RESULTS In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=-0.5 [P<.001]; 3 mg/d=-0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=-1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; -2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073). CONCLUSION These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.
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Madireddy S, Madireddy S. Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder. Int J Mol Sci 2022; 23:ijms23031844. [PMID: 35163764 PMCID: PMC8836876 DOI: 10.3390/ijms23031844] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/26/2021] [Accepted: 12/30/2021] [Indexed: 01/10/2023] Open
Abstract
Bipolar disorder (BD) is characterized by mood changes, including recurrent manic, hypomanic, and depressive episodes, which may involve mixed symptoms. Despite the progress in neurobiological research, the pathophysiology of BD has not been extensively described to date. Progress in the understanding of the neurobiology driving BD could help facilitate the discovery of therapeutic targets and biomarkers for its early detection. Oxidative stress (OS), which damages biomolecules and causes mitochondrial and dopamine system dysfunctions, is a persistent finding in patients with BD. Inflammation and immune dysfunction might also play a role in BD pathophysiology. Specific nutrient supplements (nutraceuticals) may target neurobiological pathways suggested to be perturbed in BD, such as inflammation, mitochondrial dysfunction, and OS. Consequently, nutraceuticals may be used in the adjunctive treatment of BD. This paper summarizes the possible roles of OS, mitochondrial dysfunction, and immune system dysregulation in the onset of BD. It then discusses OS-mitigating strategies that may serve as therapeutic interventions for BD. It also analyzes the relationship between diet and BD as well as the use of nutritional interventions in the treatment of BD. In addition, it addresses the use of lithium therapy; novel antipsychotic agents, including clozapine, olanzapine, risperidone, cariprazine, and quetiapine; and anti-inflammatory agents to treat BD. Furthermore, it reviews the efficacy of the most used therapies for BD, such as cognitive–behavioral therapy, bright light therapy, imagery-focused cognitive therapy, and electroconvulsive therapy. A better understanding of the roles of OS, mitochondrial dysfunction, and inflammation in the pathogenesis of bipolar disorder, along with a stronger elucidation of the therapeutic functions of antioxidants, antipsychotics, anti-inflammatory agents, lithium therapy, and light therapies, may lead to improved strategies for the treatment and prevention of bipolar disorder.
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Affiliation(s)
- Sahithi Madireddy
- Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Correspondence:
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Pavlichenko A, Gubina A. Symptomatic Profile of Cariprazine in the Context of ICD-11 Domains for Schizophrenia: Review of Clinically Oriented Studies: Симптоматический профиль карипразина в контексте доменов шизофрении в МКБ -11: обзор клинически ориентированных исследований. CONSORTIUM PSYCHIATRICUM 2022; 3:45-61. [PMID: 39045357 PMCID: PMC11262089 DOI: 10.17816/cp105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/10/2021] [Indexed: 11/08/2022] Open
Abstract
INTRODUCTION One of the innovations in the ICD-11grouping "Schizophrenia and Other Primary Psychotic Disorders" is the implementation of six symptom domains intended to improve diagnostics and treatment of these mental conditions in clinical practice. In this respect, evaluation of the effects of various psychotropic drugs, primarily antipsychotic agents, on the specified psychotic symptom domains is a critical task. The antipsychotic agent cariprazine, registered in many countries worldwide (including Russia) for schizophrenia treatment, was selected as the psychotropic drug model for the purposes of the present review. METHODS For the purposes of this review the MEDLINE, Cochrane Central Register of Controlled Trials, and PubMed databases were searched for randomized controlled trials comparing cariprazine with a placebo, or a placebo and one or several antipsychotic agents, and that was performed within the period from January 2014 to March 2021. RESULTS Cariprazine has proved its efficiency in relation to all symptom groups of the ICD-11 domain "Positive Symptoms", and may be considered a front-line therapy for treatment of the first and multiple episodes of schizophrenia, disorganized thinking, and behavioral disorders in the form of aggressiveness and hostility. Cariprazine has the best evidential base for treatment of various symptoms within the ICD-11 domain "Negative Symptoms" among all antipsychotic agents. The data with regard to the effects of cariprazine on the domain "Depressive Mood Symptoms" are controversial. No data concerning the effects of cariprazine on the domain "Manic Mood Symptoms" are available, but the effectiveness of cariprazine monotherapy for manic episodes without any psychomotor agitation signs in the instance of bipolar disorder has been demonstrated. The effectiveness of cariprazine therapy for the ICD-11 domain "Psychomotor Symptoms" has not been investigated, either within the framework of monotherapy or in the course of adjuvant therapy. The effectiveness of cariprazine has been demonstrated in treatment of the domain "Cognitive Symptoms", and the pro-cognitive effect of the drug has developed regardless of its impact on any other schizophrenia symptoms. The drug's capability to improve the functioning of patients with schizophrenia was demonstrated regardless of the impact on psychotic symptoms. CONCLUSION Cariprazine is the first-line drug for treatment of the domain "Negative Symptoms" as well as representing front-line therapy for the treatment of ICD-11 domains "Positive Symptoms" and "Cognitive Symptoms". Additional studies will be required in order to evaluate the effects of cariprazine on the ICD-11 domains "Manic Mood Symptoms" and "Depressive Mood Symptoms".
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Vannucchi T, Taddeucci C, Tatini L. Case Report: Functional and Symptomatic Improvement With Cariprazine in Various Psychiatric Patients: A Case Series. Front Psychiatry 2022; 13:878889. [PMID: 35978843 PMCID: PMC9377451 DOI: 10.3389/fpsyt.2022.878889] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
Cariprazine is a third-generation antipsychotic medication approved for the treatment of schizophrenia and bipolar disorder, with unique pharmacodynamic and pharmacokinetic properties. In this case series, the functional and symptomatic improvement of three patients who had been diagnosed with different psychiatric disorders and who exhibited various symptoms from psychotic to mood symptoms is described. The first case is about a young male patient with bipolar disorder and cocaine abuse who managed to become abstinent from cariprazine. The second and third cases describe patients with psychosis suffering from positive, cognitive and mood symptoms who were non-adherent to previous medication. In both cases, cariprazine was well-tolerated and effective in alleviating symptoms, thus improving their everyday functioning as well. In the discussion, the associations between symptom domains and the receptor profile of cariprazine are also highlighted, providing an explanation of the observed effects. It is concluded that cariprazine is a good treatment option for patients with symptoms of psychosis and addiction; is well-tolerated without the induction of side effects such as weight gain or sedation; and is appropriate for patients who have problems with adherence.
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Affiliation(s)
- Tommaso Vannucchi
- Functional Unit of Adults Mental Health, Mental Health Department, Prato, Italy
| | - Costanza Taddeucci
- Functional Unit of Adults Mental Health, Mental Health Department, Prato, Italy
| | - Lorenzo Tatini
- Functional Unit of Adults Mental Health, Mental Health Department, Prato, Italy
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Culpepper L, Vieta E, Kelly DL, Patel MD, Szatmári B, Hankinson A, Earley WR. Minimal Effects of Cariprazine on Prolactin Levels in Bipolar Disorder and Schizophrenia. Neuropsychiatr Dis Treat 2022; 18:995-1011. [PMID: 35591886 PMCID: PMC9112044 DOI: 10.2147/ndt.s348143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 04/12/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Many medications used to treat schizophrenia and bipolar I disorder are linked to hyperprolactinemia. The effects of cariprazine, a dopamine D3/D2 receptor partial agonist, on prolactin levels in patients with schizophrenia or bipolar I disorder were evaluated. METHODS Effects on prolactin were evaluated using pooled data from randomized, double-blind, placebo-controlled studies in patients with schizophrenia (4 studies; 6-week duration; cariprazine 1.5-3 mg/d, 4.5-6 mg/d, and 9-12 mg/d), bipolar mania (3 studies; 3-week duration; cariprazine 3-6 and 9-12 mg/d), and bipolar depression (3 studies; 6- to 8-week duration; cariprazine 1.5 and 3 mg/d). Long-term effects were analyzed using open-label studies in patients with schizophrenia (2 studies; 48-week duration) and patients with bipolar mania (1 study; 16-week duration). Change in prolactin levels (ng/mL) from baseline to study endpoint was evaluated in subsets of sex and prior medication use. RESULTS In patients with schizophrenia (male, n = 1377; female, n = 558), median prolactin changes were -1.2 for males and -7.4 for females on placebo, and ranged from -4.2 to -3.6 for males and -12.4 to +0.2 for females in the cariprazine-treatment groups. In patients with bipolar mania (male, n = 570; female, n = 395), median prolactin changes were -0.2 for males and -1.1 for females on placebo and ranged from -2.1 to -3.0 for males and 0 to +1.8 for females in the cariprazine-treatment groups. Median decreases were also seen in the long-term studies of schizophrenia (range, -14.6 to -2.0) and bipolar mania (range, -0.8 to +1.9). In patients with bipolar depression (male, n = 485; female, n = 780), median prolactin changes were +0.3 for males and +0.7 for females on placebo and ranged from +0.4 to +0.5 for males and +3.0 to +3.1 for females in the cariprazine-treatment groups. CONCLUSION Treatment with cariprazine for schizophrenia or bipolar I disorder was associated with minimal effects on prolactin levels.
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Affiliation(s)
| | - Eduard Vieta
- Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - Deanna L Kelly
- Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Loebel A, Koblan KS, Tsai J, Deng L, Fava M, Kent J, Hopkins SC. A Randomized, Double-blind, Placebo-controlled Proof-of-Concept Trial to Evaluate the Efficacy and Safety of Non-racemic Amisulpride (SEP-4199) for the Treatment of Bipolar I Depression. J Affect Disord 2022; 296:549-558. [PMID: 34614447 DOI: 10.1016/j.jad.2021.09.109] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/16/2021] [Accepted: 09/29/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Non-racemic amisulpride (SEP-4199) is an 85:15 ratio of aramisulpride:esamisulpride with a 5-HT7 and D2 receptor binding profile optimized for the treatment of bipolar depression. The aim of this study was to evaluate the efficacy and safety of SEP-4199 for the treatment of bipolar depression. METHODS Patients meeting DSM-5 criteria for bipolar I depression were randomized to 6 weeks of double-blind, placebo-controlled treatment with SEP-4199 200 mg/d or 400 mg/d. The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) at Week 6. The primary efficacy analysis population consisted of patients in Europe and US (n = 289); the secondary efficacy analysis population (ITT; n = 337) included patients in Japan. RESULTS Endpoint improvement in MADRS total score was observed on both the primary analysis for SEP-4199 200 mg/d (P = 0.054; effect size [ES], 0.31) and 400 mg/d (P = 0.054; ES, 0.29), and on the secondary (full ITT) analysis for SEP-4199 200 mg/d (P = 0.016; ES, 0.34) and 400 mg/d (P = 0.024; ES, 0.31). Study completion rates were 81% on SEP-4199 200 mg/d, 88% on 400 mg/d, and 86% on placebo. SEP-4199 had low rates of individual adverse events (<8%) and minimal effects on weight and lipids; median increases in prolactin were +83.6 μg/L on 200 mg/d, +95.2 μg/L on 400 mg/d compared with 0.0 μg/L on placebo. LIMITATIONS The study excluded patients with bipolar II depression and serious psychiatric or medical comorbidity. CONCLUSION Study results provide preliminary proof of concept, needing confirmation in subsequent randomized trials, for the efficacy of non-racemic amisulpride in bipolar depression.
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Affiliation(s)
- Antony Loebel
- Sunovion Pharmaceuticals Inc., Marlborough, MA, United States of America
| | - Kenneth S Koblan
- Sunovion Pharmaceuticals Inc., Marlborough, MA, United States of America.
| | - Joyce Tsai
- Sunovion Pharmaceuticals Inc., Marlborough, MA, United States of America
| | - Ling Deng
- Sunovion Pharmaceuticals Inc., Marlborough, MA, United States of America
| | - Maurizio Fava
- Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, United States of America
| | - Justine Kent
- Sunovion Pharmaceuticals Inc., Marlborough, MA, United States of America
| | - Seth C Hopkins
- Sunovion Pharmaceuticals Inc., Marlborough, MA, United States of America
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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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Cullen C, Kappelmann N, Umer M, Abdolizadeh A, Husain MO, Bonato S, Sharma G, Xue S, Ortiz A, Kloiber SM, Mulsant BH, Husain MI. Efficacy and acceptability of pharmacotherapy for comorbid anxiety symptoms in bipolar disorder: A systematic review and meta-analysis. Bipolar Disord 2021; 23:754-766. [PMID: 34506075 DOI: 10.1111/bdi.13125] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/29/2021] [Accepted: 08/28/2021] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Anxiety symptoms are highly prevalent among individuals with bipolar disorder (BD) but there is little guidance on pharmacotherapy for these symptoms. The objective of this systematic review and meta-analysis was to evaluate the available evidence for pharmacotherapy of comorbid anxiety symptoms in BD. METHODS Completed randomized clinical trials (RCTs) of medications for BD published prior to December 2020 were identified through a systematic search of MEDLINE, Embase, PsycInfo, Web of Science, clinicaltrials.gov, and the ISRCTN. Data from RCTs measuring anxiety symptoms at baseline and endpoint and all-cause discontinuation were pooled to compare the efficacy and acceptability of medications with control conditions. RESULTS Thirty-seven RCTs met our inclusion criteria; 13 placebo-controlled RCTs with 2175 participants had sufficient data to be included in the meta-analysis assessing anxiety symptoms. Compared with placebo, the overall effect size of medications (primarily atypical antipsychotics) on anxiety symptoms was small with a standardized mean difference (SMD) = -0.22 (95% CI: -0.34 to -0.11). Study heterogeneity was low (I2 = 26%). The acceptability of these medications was comparable with placebo with odds ratio of discontinuation from all causes = 0.98 (95% CI: 0.91-1.06). CONCLUSION There is limited evidence for a small anxiolytic effect and good acceptability of pharmacotherapy (primarily atypical antipsychotics) in the treatment of comorbid anxiety symptoms in BD. These results highlight the need for further research on medications other than atypical antipsychotics.
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Affiliation(s)
- Clare Cullen
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Nils Kappelmann
- Department of Research in Translational Psychiatry, Max- Planck- Institute of Psychiatry, Munich, Germany.,International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
| | - Madeha Umer
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Ali Abdolizadeh
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Muhammad Omair Husain
- Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sarah Bonato
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Gaurav Sharma
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Siqi Xue
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Abigail Ortiz
- Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Stefan M Kloiber
- Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Benoit H Mulsant
- Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Muhammad I Husain
- Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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45
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Batinic B, Ristic I, Zugic M, Baldwin DS. Treatment of Symptom Clusters in Schizophrenia, Bipolar Disorder and Major Depressive Disorder With the Dopamine D3/D2 Preferring Partial Agonist Cariprazine. Front Psychiatry 2021; 12:784370. [PMID: 34887792 PMCID: PMC8649660 DOI: 10.3389/fpsyt.2021.784370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/02/2021] [Indexed: 01/07/2023] Open
Abstract
Cariprazine is currently approved for the treatment of patients with schizophrenia (USA and EU), and for manic, depressive, and episodes with mixed features in bipolar I disorder (USA): several randomized controlled studies have also explored its efficacy in patients with major depressive disorder. This review summarizes its current therapeutic uses and potential advantages for treating the main symptoms of schizophrenia, bipolar I and major depressive disorder, considering its pharmacodynamic properties, efficacy, and tolerability. Its predominantly D3 receptor preferring affinity, with functional selectivity according to the prevailing neuronal environment, contributes to its efficacy across a wide array of psychopathological symptoms (including reality distortion, disorganized thought, negative symptoms, mood disturbance, anhedonia, and cognitive impairment), and to a favorable side effect profile. Cariprazine may be a "drug of choice" in patients with predominant negative and cognitive symptoms of schizophrenia, as well as those with metabolic syndrome. Further investigation of its relative efficacy when compared to aripiprazole or other active comparators is warranted. Its effectiveness in the treatment of bipolar mania, bipolar I depression and bipolar I episodes with mixed features, with minimal accompanying metabolic changes is well-established. The longer half-life and delayed time to relapse in patients diagnosed with schizophrenia when compared to other second-generation antipsychotics represent other advantages, given the high rates of non-adherence and frequent relapses seen in clinical practice. Its efficacy in overlapping symptom domains in other major psychiatric disorders appears promising.
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Affiliation(s)
- Borjanka Batinic
- Clinic of Psychiatry, University Clinical Centre of Serbia, Belgrade, Serbia
- Department of Psychology, Faculty of Philosophy, University of Belgrade, Belgrade, Serbia
| | - Ivan Ristic
- Department of Epidemiology, Medical School, University of Belgrade, Belgrade, Serbia
- Department of Psychiatry, Institute of Mental Health, Belgrade, Serbia
| | - Milica Zugic
- Department of Psychiatry, Institute of Mental Health, Belgrade, Serbia
| | - David S. Baldwin
- Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
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46
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Prokop S, Ábrányi-Balogh P, Barti B, Vámosi M, Zöldi M, Barna L, Urbán GM, Tóth AD, Dudok B, Egyed A, Deng H, Leggio GM, Hunyady L, van der Stelt M, Keserű GM, Katona I. PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells. Nat Commun 2021; 12:6505. [PMID: 34764251 PMCID: PMC8586358 DOI: 10.1038/s41467-021-26757-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 09/30/2021] [Indexed: 12/25/2022] Open
Abstract
Immunolabeling and autoradiography have traditionally been applied as the methods-of-choice to visualize and collect molecular information about physiological and pathological processes. Here, we introduce PharmacoSTORM super-resolution imaging that combines the complementary advantages of these approaches and enables cell-type- and compartment-specific nanoscale molecular measurements. We exploited rational chemical design for fluorophore-tagged high-affinity receptor ligands and an enzyme inhibitor; and demonstrated broad PharmacoSTORM applicability for three protein classes and for cariprazine, a clinically approved antipsychotic and antidepressant drug. Because the neurobiological substrate of cariprazine has remained elusive, we took advantage of PharmacoSTORM to provide in vivo evidence that cariprazine predominantly binds to D3 dopamine receptors on Islands of Calleja granule cell axons but avoids dopaminergic terminals. These findings show that PharmacoSTORM helps to quantify drug-target interaction sites at the nanoscale level in a cell-type- and subcellular context-dependent manner and within complex tissue preparations. Moreover, the results highlight the underappreciated neuropsychiatric significance of the Islands of Calleja in the ventral forebrain.
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Affiliation(s)
- Susanne Prokop
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
- School of Ph.D. Studies, Semmelweis University, Budapest, Hungary
| | - Péter Ábrányi-Balogh
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary
| | - Benjámin Barti
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
- School of Ph.D. Studies, Semmelweis University, Budapest, Hungary
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Márton Vámosi
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
| | - Miklós Zöldi
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
- School of Ph.D. Studies, Semmelweis University, Budapest, Hungary
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - László Barna
- Nikon Center of Excellence for Neuronal Imaging, Institute of Experimental Medicine, Budapest, Hungary
| | - Gabriella M Urbán
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
| | - András Dávid Tóth
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- MTA-SE Laboratory of Molecular Physiology, Eötvös Loránd Research Network, Budapest, Hungary
| | - Barna Dudok
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
- Department of Neurosurgery, Stanford University, Stanford, CA, USA
| | - Attila Egyed
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary
| | - Hui Deng
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, Leiden, the Netherlands
| | - Gian Marco Leggio
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy
| | - László Hunyady
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- MTA-SE Laboratory of Molecular Physiology, Eötvös Loránd Research Network, Budapest, Hungary
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, Leiden, the Netherlands
| | - György M Keserű
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary
| | - István Katona
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary.
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
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47
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Dubovsky SL, Ghosh BM, Serotte JC, Cranwell V. Psychotic Depression: Diagnosis, Differential Diagnosis, and Treatment. PSYCHOTHERAPY AND PSYCHOSOMATICS 2021; 90:160-177. [PMID: 33166960 DOI: 10.1159/000511348] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 08/30/2020] [Indexed: 11/19/2022]
Abstract
Psychotic depression was initially considered to be at one end of a continuum of severity of major depression. Subsequent experience demonstrated that psychosis is an independent trait that may accompany mood disorders of varying severity. While much has been learned about the impact of severe mood congruent delusions and hallucinations on the course and treatment response of depression, less is known about fleeting or mild psychosis, mood incongruent features, or psychotic symptoms that reflect traumatic experiences. Acute treatment of psychotic unipolar depression generally involves the combination of an antidepressant and an antipsychotic drug or electroconvulsive therapy. There is inadequate information about maintenance treatment of unipolar psychotic depression and acute and chronic treatment of psychotic bipolar disorder. Decision-making therefore still must rely in part on clinical experience.
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Affiliation(s)
- Steven L Dubovsky
- Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA, .,Departments of Psychiatry and Medicine, University of Colorado School of Medicine, Denver, Colorado, USA,
| | - Biswarup M Ghosh
- Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Jordan C Serotte
- Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Victoria Cranwell
- Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
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48
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Cookson J, Pimm J. Partial agonists of dopamine receptors: mechanisms and clinical effects of aripiprazole, brexpiprazole and cariprazine. BJPSYCH ADVANCES 2021. [DOI: 10.1192/bja.2021.49] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
SUMMARY
Aripiprazole, brexpiprazole and cariprazine are partial dopamine (and serotonin) agonists developed as novel antipsychotics. This article discusses their pharmacology, evidence on their licensed and off-licence uses (including psychosis, mania, bipolar depression, Tourette syndrome and autism spectrum disorder) and side-effects. In schizophrenia, they have a low risk of Parkinsonism or hyperprolactinaemia, cause modest increases in body weight and are of moderate efficacy.
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49
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Vieta E, Calabrese JR, Whelan J, Tohen M, Earley WR. The efficacy of cariprazine on function in patients with bipolar depression: a post hoc analysis of a randomized controlled trial. Curr Med Res Opin 2021; 37:1635-1643. [PMID: 34034612 DOI: 10.1080/03007995.2021.1932446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Individuals with bipolar depression often experience functional impairment that interferes with recovery. These analyses examined the effects of cariprazine on functional outcomes in patients with bipolar I disorder. METHODS Prespecified analyses of data from a randomized, double-blind, placebo-controlled pivotal trial of cariprazine in bipolar I depression (NCT01396447) evaluated mean changes from baseline to week 8 in Functional Assessment Short Test (FAST) total score. Post hoc analyses with no adjustment for multiplicity evaluated FAST subscale scores, functional recovery and remission (FAST total score ≤11 and ≤20, respectively), and 30% or 50% improvement from baseline. RESULTS There were 393 patients with bipolar I disorder (placebo = 132; cariprazine: 1.5 mg/d = 135, 3 mg/d = 126) in the FAST analysis population. Statistically significant differences were noted for cariprazine 1.5 mg/d versus placebo in mean change from baseline in FAST total score (p<.01) and on 5 of 6 subscale scores (p<.05); cariprazine 3 mg/d was significantly different than placebo on the Interpersonal Relationship subscale (p<.05). Rates of functional remission and recovery, and ≥30% or ≥50% improvement were significantly greater for cariprazine 1.5 mg/d versus placebo (p<.05 all); the percentage of patients with ≥30% improvement was significantly different for cariprazine 3 mg/d versus placebo (p<.05). CONCLUSION At week 8, statistically significant improvements in FAST outcomes were observed for cariprazine versus placebo in patients with bipolar I depression; more consistent results were noted for 1.5 mg/d than 3 mg/d. In addition to improving bipolar depression symptoms, these results suggest that cariprazine may improve functional outcomes.
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Affiliation(s)
- Eduard Vieta
- Department of Psychiatry and Psychology, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Joseph R Calabrese
- Mood Disorders Program, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Jessica Whelan
- Department of Nursing, Maryville University, Saint Louis, MO, USA
- Holon Inclusive Health Care, Dupo, IL, USA
| | - Mauricio Tohen
- Department of Psychiatry and Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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50
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Angarita GA, Hadizadeh H, Cerdena I, Potenza MN. Can pharmacotherapy improve treatment outcomes in people with co-occurring major depressive and cocaine use disorders? Expert Opin Pharmacother 2021; 22:1669-1683. [PMID: 34042556 DOI: 10.1080/14656566.2021.1931684] [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: 10/21/2022]
Abstract
Introduction: Major depressive disorder (MDD) and cocaine use disorder (CUD) are prevalent and frequently co-occur. When co-occurring, the presence of one disorder typically negatively impacts the prognosis for the other. Given the clinical relevance, we sought to examine pharmacotherapies for co-occurring CUD and MDD. While multiple treatment options have been examined in the treatment of each condition individually, studies exploring pharmacological options for their comorbidity are fewer and not conclusive.Areas Covered: For this review, the authors searched the literature in PubMed using clinical query options for therapies and keywords relating to each condition. Then, they described potentially promising pharmacologic therapeutic options based on shared mechanisms between the two conditions and/or results from individual clinical trials conducted to date.Expert opinion: Medications like stimulants, dopamine (D3) receptors partial agonists or antagonists, antagonists of kappa opioid receptors, topiramate, and ketamine could be promising as there is significant overlap relating to reward deficiency models, antireward pathways, and altered glutamatergic systems. However, the available clinical literature on any one of these types of agents is mixed. Additionally, for some agents there is possible concern related to abuse potential (e.g. ketamine and stimulants).
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Affiliation(s)
- Gustavo A Angarita
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, CT, USA
| | - Hasti Hadizadeh
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, CT, USA
| | - Ignacio Cerdena
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,Connecticut Mental Health Center, New Haven, CT, USA
| | - Marc N Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,Connecticut Mental Health Center, New Haven, CT, USA.,Child Study Center, Yale University School of Medicine, New Haven, CT, USA.,Department of Neuroscience, Yale University, New Haven, CT, USA.,Connecticut Council on Problem Gambling, Wethersfield, CT, USA
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