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Xu JW, Guan XB, Wang XY, Feng Y, Zhang Q, Zhu JJ, Chen JH. Relationship between plasma risperidone concentrations and clinical features in chronic schizophrenic patients in China. World J Psychiatry 2024; 14:523-532. [PMID: 38659603 PMCID: PMC11036455 DOI: 10.5498/wjp.v14.i4.523] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/07/2024] [Accepted: 03/22/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Prior studies have noted great variability in the plasma levels of risperidone (RIS). Plasma concentrations of RIS and its active moiety are highly variable and depend on absorption, metabolism, and other predictors of metabolic dysregulation; however, these factors are poorly understood and the association between metabolic change and change in psychopathology is uncertain. AIM To ascertain the characteristics of chronic schizophrenic patients treated with RIS, and to assess their relationship with plasma RIS levels. METHODS This was a descriptive cross-sectional study of 50 patients with a diagnosis of schizophrenic psychosis treated with RIS in a psychiatric service. The plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone were determined by high performance liquid chromatography. The patients' demographic and clinical characteristics, and psychopathologies were assessed, and the associations between clinical variables and plasma levels of RIS were explored. RESULTS Male patients received higher doses of RIS than female ones, but plasma concentrations of RIS and risperidone + 9-hydroxyrisperidone (active moiety) were higher in female patients. Age and the mean scores of the general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS) were significantly positively correlated with plasma concentrations of risperidone + 9-hydroxyrisperidone adjusted for weight and dose in all 50 subjects. In male subjects, we found a statistically significant positive correlation between the concentrations of risperidone + 9-hydroxyrisperidone in plasma/(dose × kg) and age, mean PANSS negative subscale scores, mean PANSS general psychopathology subscale scores, and mean PANSS total scores. CONCLUSION Long-term use of RIS should be closely monitored in older patients and females to minimize the risk of high concentrations which could induce side effects.
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Affiliation(s)
- Jing-Wen Xu
- Department of Medicine, Shanghai No. 3 Mental Health Center of Civil Administration, Shanghai 200435, China
| | - Xiao-Bo Guan
- The Fourth Sick Ward, Shanghai No. 3 Mental Health Center of Civil Administration, Shanghai 200435, China
| | - Xue-Ying Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai 200030, China
| | - Yang Feng
- The First Sick Ward, Shanghai No. 3 Mental Health Center of Civil Administration, Shanghai 200435, China
| | - Qi Zhang
- Department of Medicine, Shanghai No. 3 Mental Health Center of Civil Administration, Shanghai 200435, China
| | - Jun-Juan Zhu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai 200030, China
| | - Jian-Hua Chen
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai 200030, China
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2
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Vartzoka F, Ozenoglu E, Pitsikas N. The Nitric Oxide (NO) Donor Molsidomine Attenuates Memory Impairments Induced by the D1/D2 Dopaminergic Receptor Agonist Apomorphine in the Rat. Molecules 2023; 28:6861. [PMID: 37836704 PMCID: PMC10574075 DOI: 10.3390/molecules28196861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/27/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D1/D2 receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia.
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Affiliation(s)
- Foteini Vartzoka
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Panepistimiou 3, 415-00 Larissa, Greece
| | - Elif Ozenoglu
- School of Medicine, University of Acibadem, 415-00 Istanbul, Turkey
| | - Nikolaos Pitsikas
- Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Panepistimiou 3, 415-00 Larissa, Greece
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3
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Guo S, Li K, Chen Y, Li B. Unraveling the drug distribution in brain enabled by MALDI MS imaging with laser-assisted chemical transfer. Acta Pharm Sin B 2022; 12:2120-2126. [PMID: 35847487 PMCID: PMC9279630 DOI: 10.1016/j.apsb.2021.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/24/2021] [Accepted: 11/03/2021] [Indexed: 12/15/2022] Open
Abstract
Accurate localization of central nervous system (CNS) drug distribution in the brain is quite challenging to matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI), owing to the ionization competition/suppression of highly abundant endogenous biomolecules and MALDI matrix. Herein, we developed a highly efficient sample preparation technique, laser-assisted chemical transfer (LACT), to enhance the detection sensitivity of CNS drugs in brain tissues. A focused diode laser source transilluminated the tissue slide coated with α-cyano-4-hydroxycinnamic acid, an optimal matrix to highly absorb the laser radiation at 405 nm, and a very thin-layer chemical film mainly containing drug molecule was transferred to the acceptor glass slide. Subsequently, MALDI MSI was performed on the chemical film without additional sample treatment. One major advantage of LACT is to minimize ionization competition/suppression from the tissue itself by removing abundant endogenous lipid and protein components. The superior performance of LACT led to the successful visualization of regional distribution patterns of 16 CNS drugs in the mouse brain. Furthermore, the dynamic spatial changes of risperidone and its metabolite were visualized over a 24-h period. Also, the brain-to-plasma (B/P) ratio could be obtained according to MALDI MSI results, providing an alternative means to assess brain penetration in drug discovery.
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4
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Taurines R, Fekete S, Preuss-Wiedenhoff A, Warnke A, Wewetzer C, Plener P, Burger R, Gerlach M, Romanos M, Egberts KM. Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone. J Neural Transm (Vienna) 2022; 129:689-701. [PMID: 35303169 PMCID: PMC9188514 DOI: 10.1007/s00702-022-02485-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/24/2022] [Indexed: 01/31/2023]
Abstract
Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose–concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20–60 ng/ml) is applicable for minors. In the 64 patients (aged 11–18 years) included, a positive correlation between daily dose and the active moiety (RISam) concentration was found (rs = 0.49, p = 0.001) with variation in dose explaining 24% (rs2 = 0.240) of the variability in serum concentrations. While the RISam concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RISam was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.
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Affiliation(s)
- R Taurines
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany
| | - S Fekete
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany
| | - A Preuss-Wiedenhoff
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany
| | - A Warnke
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany
| | - C Wewetzer
- Clinic for Child and Adolescent Psychiatry and Psychotherapy, Clinics of the City Cologne GmbH, Cologne, Germany
| | - P Plener
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Ulm, Ulm, Germany.,Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria
| | - R Burger
- Department of Psychiatry, Psychosomatics and Psychotherapy, Laboratory for Therapeutic Drug Monitoring, Centre for Mental Health, University Hospital of Wuerzburg, Wuerzburg, Germany
| | - M Gerlach
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany
| | - M Romanos
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany
| | - K M Egberts
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany.
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A comparison of the metabolic side-effects of the second-generation antipsychotic drugs risperidone and paliperidone in animal models. PLoS One 2021; 16:e0246211. [PMID: 33508013 PMCID: PMC7842964 DOI: 10.1371/journal.pone.0246211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 01/14/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals. METHODS Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp. RESULTS Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance. CONCLUSIONS In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.
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Kimura H, Kanahara N, Iyo M. Rationale and neurobiological effects of treatment with antipsychotics in patients with chronic schizophrenia considering dopamine supersensitivity. Behav Brain Res 2021; 403:113126. [PMID: 33460681 DOI: 10.1016/j.bbr.2021.113126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
The long-term treatment of patients with schizophrenia often involves the management of relapses for most patients and the development of treatment resistance in some patients. To stabilize the clinical course and allow as many patients as possible to recover, clinicians need to recognize dopamine supersensitivity, which can be provoked by administration of high dosages of antipsychotics, and deal with it properly. However, no treatment guidelines have addressed this issue. The present review summarized the characteristics of long-acting injectable antipsychotics, dopamine partial agonists, and clozapine in relation to dopamine supersensitivity from the viewpoints of receptor profiles and pharmacokinetics. The potential merits and limitations of these medicines are discussed, as well as the risks of treating patients with established dopamine supersensitivity with these classes of drugs. Finally, the review discussed the biological influence of antipsychotic treatment on the human brain based on findings regarding the relationship between the hippocampus and antipsychotics.
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Affiliation(s)
- Hiroshi Kimura
- Department of Psychiatry, School of Medicine, International University of Health and Welfare, Chiba, Japan; Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Psychiatry, Gakuji-kai Kimura Hospital, Chiba, Japan.
| | - Nobuhisa Kanahara
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
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7
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Rub RA, Beg S, Kazmi I, Afzal O, Almalki WH, Alghamdi S, Akhter S, Ali A, Ahmed FJ. Systematic development of a bioanalytical UPLC-MS/MS method for estimation of risperidone and its active metabolite in long-acting microsphere formulation in rat plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2020; 1160:122433. [PMID: 33212399 DOI: 10.1016/j.jchromb.2020.122433] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/18/2020] [Accepted: 10/21/2020] [Indexed: 10/23/2022]
Abstract
A systematic approach to develop a UPLC-MS/MS method was applied for quantifying of risperidone (RISP), its active metabolite, 9-hydroxy risperidone (9-OH-RISP) and internal standard (propranolol) in rat plasma. Liquid-liquid extraction was performed using methyl tert-butyl ether for quantification of drug and its active metabolite by MS detection in the positive ion mode. Acquity UPLC system with BEH C18 (2.1 mm × 100 mm, particle size 1.7 μm) column was used along with acetonitrile (0.1% formic acid)-2 mM (milli mole) ammonium acetate in isocratic condition was used as the mobile phase. Detection was performed by multiple reactions monitoring with precursor-to-product ion transitions with m/z 411.2 → 191.0 for RISP, m/z 427.2 → 207.0 for 9-OH-RISP and m/z 260.1 → 116.0 for IS. The method was validated as per the FDA guidance on bioanalytical method validation. Linearity (r2 = 0.999) was observed in the drug concentration ranging between 0.1 and 50 ng mL-1, while all other parameters were found to be within the acceptable ranges. Method robustness was optimized by Box-Behnken design to monitor the influential variables to achieve maximal recovery of the analytes in the rat plasma. Pharmacokinetic evaluation of the analytes from long-acting microparticles in rat plasma showed two peaks indicating an initial burst effect within 24 h of administration followed by controlled drug release pattern upto 45 days, while marketed formulation (Risperdal Consta®) showed no plasma concentration during the lag-time of 21 days followed by maximal drug absorption between 28 and 40 days.
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Affiliation(s)
- Rehan Abdur Rub
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Sarwar Beg
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, AlKharj, Saudi Arabia
| | - Waleed H Almalki
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura, University, Saudi Arabia
| | - Saad Alghamdi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura, University, Saudi Arabia
| | - Sohail Akhter
- Centre de Biophysique Moléculaire, CNRS UPR4301, Rue Charles Sadron, Orléans Cedex 2, France
| | - Asgar Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Farhan J Ahmed
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
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A fast DLLME-LC-MS/MS method for risperidone and its metabolite 9-hydroxyrisperidone determination in plasma samples for therapeutic drug monitoring of patients. Microchem J 2020. [DOI: 10.1016/j.microc.2020.104894] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Pharmacokinetics and pharmacodynamics evaluation on risperidone-containing microsphere fabricated by ultra-fine particle processing system. POWDER TECHNOL 2019. [DOI: 10.1016/j.powtec.2018.08.072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Wesołowska A, Jastrzębska-Więsek M, Cios A, Partyka A. The preclinical discovery and development of paliperidone for the treatment of schizophrenia. Expert Opin Drug Discov 2019; 15:279-292. [DOI: 10.1080/17460441.2020.1682994] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Anna Wesołowska
- Jagiellonian University Medical College, Department of Clinical Pharmacy, Kraków, Poland
| | | | - Agnieszka Cios
- Jagiellonian University Medical College, Department of Clinical Pharmacy, Kraków, Poland
| | - Anna Partyka
- Jagiellonian University Medical College, Department of Clinical Pharmacy, Kraków, Poland
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Abstract
After the identification of the influence of serotonergic receptors in ameliorating the negative symptoms associated with schizophrenia, atypical antipsychotics were developed by incorporating dopamine and serotonin antagonism. Risperidone, sold under the trade name Risperdal, was the second atypical antipsychotic developed following clozapine but quickly became a first-line treatment for acute and chronic schizophrenia because of its preferential side effect profile. Despite initial Food and Drug Administration approval 25 years ago, risperidone continues to be a fundamental treatment for schizophrenia, bipolar I disorder, and autism-related irritability. It is on the World Health Organization's List of Essential Medicines for its balance of efficacy, safety, tolerability, and cost-effectiveness. In this review, we highlight the history and importance of risperidone as an atypical antipsychotic, in addition to its chemical synthesis, manufacturing, drug metabolism and pharmacokinetics, pharmacology, structure-activity relationship, indications, and adverse effects.
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Affiliation(s)
- Trevor C. Chopko
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Craig W. Lindsley
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
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12
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Ji WH, Guo YS, Wang X, Guo DS. A water-compatible magnetic molecularly imprinted polymer for the selective extraction of risperidone and 9-hydroxyrisperidone from human urine. Talanta 2018; 181:392-400. [DOI: 10.1016/j.talanta.2018.01.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 01/06/2018] [Accepted: 01/10/2018] [Indexed: 01/23/2023]
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Abstract
Early-life administration of risperidone, the most widely used antipsychotic drug in children, leads to persistently elevated locomotor activity in adult rats. This study determined whether and when elevated locomotor activity emerges during developmental risperidone administration. Developing and adult rats were administered daily injections of risperidone (1.0 and 3.0 mg/kg) or vehicle for 4 weeks beginning at postnatal days 14 and 74, respectively. Starting with the first injection and every 7 days thereafter, locomotor activity was measured immediately after the injection and 20 min before the next day's injection. Activity was also recorded 1 week after the final injection. Risperidone markedly decreased locomotor activity in developing and adult rats immediately after injection. Within 24 h after their first injection, adult rats administered risperidone showed greater activity levels. In contrast, developing rats did not show compensatory hyperactivity until the beginning of the fourth week of risperidone administration. One week after the final risperidone injection, there was no evidence of hyperactivity in the adult rats maintained on risperidone, but developing rats administered risperidone, especially females, showed greater activity levels relative to vehicle-administered controls. In comparison with adult rats, the emergence of compensatory hyperactivity during long-term antipsychotic drug administration is delayed in developing rats, but persists after treatment cessation.
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Nørbak-Emig H, Pinborg LH, Raghava JM, Svarer C, Baaré WFC, Allerup P, Friberg L, Rostrup E, Glenthøj B, Ebdrup BH. Extrastriatal dopamine D 2/3 receptors and cortical grey matter volumes in antipsychotic-naïve schizophrenia patients before and after initial antipsychotic treatment. World J Biol Psychiatry 2017; 18:539-549. [PMID: 27782768 DOI: 10.1080/15622975.2016.1237042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Long-term dopamine D2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D2/3 receptor binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment. METHODS Twenty-two initially antipsychotic-naïve patients underwent magnetic resonance imaging (MRI), [123I]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N = 13) or zuclopenthixol (N = 9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT. RESULTS Neither extrastriatal D2/3 receptor BPND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post-hoc analyses excluding three patients with cannabis use we found that higher D2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume. CONCLUSIONS The present data do not support an association between extrastriatal D2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies.
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Affiliation(s)
- Henrik Nørbak-Emig
- a Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre, Glostrup, University of Copenhagen , Denmark.,b Faculty of Health and Medical Sciences, Department of Clinical Medicine , University of Copenhagen , Denmark
| | - Lars H Pinborg
- c Neurobiology Research Unit and Epilepsy Clinic, Rigshospitalet, University of Copenhagen , Denmark
| | - Jayachandra M Raghava
- a Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre, Glostrup, University of Copenhagen , Denmark.,d Functional Imaging Unit, Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet - Glostrup , University of Copenhagen , Denmark
| | - Claus Svarer
- c Neurobiology Research Unit and Epilepsy Clinic, Rigshospitalet, University of Copenhagen , Denmark
| | - William F C Baaré
- e Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen , Denmark
| | - Peter Allerup
- f Institute for Education (DPU), Aarhus University , Denmark
| | - Lars Friberg
- g Department of Clinical Physiology and Nuclear Medicine , Bispebjerg Hospital, University of Copenhagen , Denmark
| | - Egill Rostrup
- d Functional Imaging Unit, Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet - Glostrup , University of Copenhagen , Denmark
| | - Birte Glenthøj
- a Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre, Glostrup, University of Copenhagen , Denmark.,b Faculty of Health and Medical Sciences, Department of Clinical Medicine , University of Copenhagen , Denmark
| | - Bjørn H Ebdrup
- a Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre, Glostrup, University of Copenhagen , Denmark
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15
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Horska K, Ruda-Kucerova J, Karpisek M, Suchy P, Opatrilova R, Kotolova H. Depot risperidone-induced adverse metabolic alterations in female rats. J Psychopharmacol 2017; 31:487-499. [PMID: 28347258 DOI: 10.1177/0269881117691466] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Atypical antipsychotics are associated with adverse metabolic effects including weight gain, increased adiposity, dyslipidaemia, alterations in glucose metabolism and insulin resistance. Increasing evidence suggests that metabolic dysregulation precedes weight gain development. The aim of this study was to evaluate alterations in adipokines, hormones and basic serum biochemical parameters induced by chronic treatment with depot risperidone at two doses (20 and 40 mg/kg) in female Sprague-Dawley rats. Dose-dependent metabolic alterations induced by risperidone after 6 weeks of treatment were revealed. Concomitant to weight gain and increased liver weight, an adverse lipid profile with an elevated triglyceride level was observed in the high exposure group, administered a 40 mg/kg dose repeatedly, while the low dose exposure group, administered a 20 mg/kg dose, developed weight gain without alterations in the lipid profile and adipokine levels. An initial peak in leptin serum level after the higher dose was observed in the absence of weight gain. This finding may indicate that the metabolic alterations observed in this study are not consequent to body weight gain. Taken together, these data may support the primary effects of atypical antipsychotics on peripheral tissues.
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Affiliation(s)
- Katerina Horska
- 1 Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Jana Ruda-Kucerova
- 2 Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Michal Karpisek
- 1 Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic.,3 R&D Department, Biovendor - Laboratorni Medicina, Brno, Czech Republic
| | - Pavel Suchy
- 1 Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Radka Opatrilova
- 4 Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Hana Kotolova
- 1 Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
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16
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Shimizu S, den Hoedt SM, Mangas-Sanjuan V, Cristea S, Geuer JK, van den Berg DJ, Hartman R, Bellanti F, de Lange ECM. Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat. Drug Metab Dispos 2017; 45:152-159. [PMID: 27836941 DOI: 10.1124/dmd.116.072306] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/07/2016] [Indexed: 11/22/2022] Open
Abstract
To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD). PK and PKPD modeling was performed by nonlinear mixed-effect modeling. Plasma, brain ECF, and CSF PK values of RIS and PAL were well described by a 12-compartmental semi-PBPK model, including metabolic conversion of RIS to PAL. P-gp efflux functionality was identified on brain ECF for RIS and PAL and on CSF only for PAL. In the PKPD analysis, the plasma drug concentrations were more relevant than brain ECF or CSF concentrations to explain the prolactin response; the estimated EC50 was in accordance with reports in the literature for both RIS and PAL. We conclude that for RIS and PAL, the plasma concentrations better explain the prolactin response than do brain ECF or CSF concentrations. This research shows that PKPD modeling is of high value to delineate the target site of drugs.
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Affiliation(s)
- Shinji Shimizu
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Sandra M den Hoedt
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Victor Mangas-Sanjuan
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Sinziana Cristea
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Jana K Geuer
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Dirk-Jan van den Berg
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Robin Hartman
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Francisco Bellanti
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Elizabeth C M de Lange
- Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands
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17
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Sedative effect of Clozapine is a function of 5-HT 2A and environmental novelty. Eur Neuropsychopharmacol 2017; 27:70-81. [PMID: 27955831 DOI: 10.1016/j.euroneuro.2016.10.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 09/06/2016] [Accepted: 10/29/2016] [Indexed: 12/20/2022]
Abstract
Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT2A knockout (Htr2a-/-) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a-/- mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being 'novel'. In their 'home' environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol-induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a+/+ mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the 'novel' context. Our study establishes a previously unknown interaction between the environmental context, 5-HT2A and CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation.
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18
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Puangpetch A, Vanwong N, Nuntamool N, Hongkaew Y, Chamnanphon M, Sukasem C. CYP2D6 polymorphisms and their influence on risperidone treatment. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2016; 9:131-147. [PMID: 27942231 PMCID: PMC5138038 DOI: 10.2147/pgpm.s107772] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cytochrome P450 enzyme especially CYP2D6 plays a major role in biotransformation. The interindividual variations of treatment response and toxicity are influenced by the polymorphisms of this enzyme. This review emphasizes the effect of CYP2D6 polymorphisms in risperidone treatment in terms of basic knowledge, pharmacogenetics, effectiveness, adverse events, and clinical practice. Although the previous studies showed different results, the effective responses in risperidone treatment depend on the CYP2D6 polymorphisms. Several studies suggested that CYP2D6 polymorphisms were associated with plasma concentration of risperidone, 9-hydroxyrisperidone, and active moiety but did not impact on clinical outcomes. In addition, CYP2D6 poor metabolizer showed more serious adverse events such as weight gain and prolactin than other predicted phenotype groups. The knowledge of pharmacogenomics of CYP2D6 in risperidone treatment is increasing, and it can be used for the development of personalized medication in term of genetic-based dose recommendation. Moreover, the effects of many factors in risperidone treatment are still being investigated. Both the CYP2D6 genotyping and therapeutic drug monitoring are the important steps to complement the genetic-based risperidone treatment.
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Affiliation(s)
- Apichaya Puangpetch
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital
| | - Natchaya Vanwong
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital
| | - Nopphadol Nuntamool
- Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Yaowaluck Hongkaew
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital
| | - Monpat Chamnanphon
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital
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19
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Weng W, Quan P, Liu C, Zhao H, Fang L. Design of a Drug-in-Adhesive Transdermal Patch for Risperidone: Effect of Drug-Additive Interactions on the Crystallization Inhibition and In Vitro / In Vivo Correlation Study. J Pharm Sci 2016; 105:3153-3161. [DOI: 10.1016/j.xphs.2016.07.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 07/03/2016] [Accepted: 07/06/2016] [Indexed: 11/24/2022]
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20
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Sawant-Basak A, Chen L, Shaffer CL, Palumbo D, Schmidt A, Tseng E, Spracklin DK, Gallezot JD, Labaree D, Nabulsi N, Huang Y, Carson RE, McCarthy T. Quantitative projection of human brain penetration of the H3 antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy. Xenobiotica 2016; 47:119-126. [DOI: 10.3109/00498254.2016.1166531] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Aarti Sawant-Basak
- Departments of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA, USA,
| | - Laigao Chen
- Clinical & Translational Imaging, Pfizer Inc., Cambridge, MA, USA,
| | | | - Donna Palumbo
- Worldwide Research and Development, Pfizer Inc., Cambridge, MA, USA, and
| | - Anne Schmidt
- Departments of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA, USA,
| | - Elaine Tseng
- Departments of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA, USA,
| | - Douglas K. Spracklin
- Departments of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA, USA,
| | | | - David Labaree
- Department of Diagnostic Radiology, Yale University, New Haven, CT, USA
| | - Nabeel Nabulsi
- Department of Diagnostic Radiology, Yale University, New Haven, CT, USA
| | - Yiyun Huang
- Department of Diagnostic Radiology, Yale University, New Haven, CT, USA
| | - Richard E. Carson
- Department of Diagnostic Radiology, Yale University, New Haven, CT, USA
| | - Timothy McCarthy
- Clinical & Translational Imaging, Pfizer Inc., Cambridge, MA, USA,
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21
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Onozato M, Nakazawa H, Hakariya H, Shishikura M, Nagashima C, Ishimaru K, Sakamoto T, Iizuka H, Ichiba H, Fukushima T. Effect of risperidone on plasma d-serine concentration in rats post-administered with d-serine. Life Sci 2016; 158:98-103. [PMID: 27352936 DOI: 10.1016/j.lfs.2016.06.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 06/14/2016] [Accepted: 06/23/2016] [Indexed: 11/30/2022]
Abstract
AIMS Risperidone (Ris) is a second-generation antipsychotic (SGA) used to treat patients with schizophrenia. Additional interventions that increase plasma d-serine (d-Ser) levels could provide improved amelioration of the negative symptoms of schizophrenia. In the present study, we studied whether Ris pretreatment altered the concentration of plasma d-Ser administered intraperitoneally. In addition, the effects of Ris and its main metabolite, 9-hydroxyrisperidone (9-OHRis), on rat d-amino acid oxidase (DAO) activity were examined in vitro. MATERIALS AND METHODS Ris (0, 0.5, 1.0, or 3.0mg/kg), followed by d-Ser (20mg/kg), were administered intraperitoneally (i.p.) to male Sprague-Dawley rats, and the time-courses of plasma d-Ser, Ris, and 9-OHRis concentrations were examined. Inhibition of DAO activity in rat cerebellar and kidney preparations by Ris and 9-OHRis were measured spectrophotometrically. KEY FINDINGS Significant increases in plasma d-Ser levels were observed in rats treated with both Ris and d-Ser. This effect occurred in a Ris dose-dependent manner, and the areas under the plasma d-Ser concentration-time curves were similar in rats treated with Ris (1.0mg/kg) and with a commercial DAO inhibitor, 3-methylpyrazole-5-carboxylic acid (1.0mg/kg). Rat plasma analyses showed that 9-OHRis was rapidly produced from Ris; however, high concentrations of Ris and 9-OHRis produced weak DAO inhibition in vitro, suggesting that some other pharmacological effect of Ris and/or 9-OHRis might contribute to its effects on plasma d-Ser levels. SIGNIFICANCE The combined administration of Ris and d-Ser may increase plasma d-Ser levels, suggesting that this approach could reduce the dose of d-Ser required for these patients.
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Affiliation(s)
- Mayu Onozato
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Hiromi Nakazawa
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Hitomi Hakariya
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Miho Shishikura
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Chihiro Nagashima
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Katsuyuki Ishimaru
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Tatsuya Sakamoto
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Hideaki Iizuka
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Hideaki Ichiba
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan
| | - Takeshi Fukushima
- Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan.
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22
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Molden E, Waade RB, Hoff M, Haslemo T. Impact of Ageing on Serum Concentrations of Risperidone and Its Active Metabolite in Patients with KnownCYP2D6Genotype. Basic Clin Pharmacol Toxicol 2016; 119:470-475. [DOI: 10.1111/bcpt.12614] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 04/28/2016] [Indexed: 12/01/2022]
Affiliation(s)
- Espen Molden
- Center for Psychopharmacology; Diakonhjemmet Hospital; Oslo Norway
- Department of Pharmaceutical Biosciences; School of Pharmacy; University of Oslo; Oslo Norway
| | | | - Maren Hoff
- Department of Pharmaceutical Biosciences; School of Pharmacy; University of Oslo; Oslo Norway
| | - Tore Haslemo
- Center for Psychopharmacology; Diakonhjemmet Hospital; Oslo Norway
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23
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Vanwong N, Ngamsamut N, Hongkaew Y, Nuntamool N, Puangpetch A, Chamnanphon M, Sinrachatanant A, Limsila P, Sukasem C. Detection of CYP2D6 polymorphism using Luminex xTAG technology in autism spectrum disorder: CYP2D6 activity score and its association with risperidone levels. Drug Metab Pharmacokinet 2016; 31:156-62. [PMID: 26944100 DOI: 10.1016/j.dmpk.2016.01.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 01/25/2016] [Accepted: 01/28/2016] [Indexed: 11/19/2022]
Abstract
CYP2D6 is involved in the biotransformation of a large number of drugs, including risperidone. This study was designed to detect CYP2D6 polymorphisms with a Luminex assay, including assessment the relationship of CYP2D6 polymorphisms and risperidone plasma concentration in autism spectrum disorder children (ASD) treated with risperidone. All 84 ASD patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by Luminex assay. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Among the 84 patients, there were 46 (55.42%) classified as EM, 33 (39.76%) as IM, and 4(4.82%) as UM. The plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients were significant differences among the CYP2D6 predicted phenotype group (P = 0.001 and P < 0.0001 respectively). Moreover, the plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients with CYP2D6 activity score 0.5 were significantly higher than those with the CYP2D6 activity score 2.0 (P = 0.004 and P = 0.002 respectively). These findings suggested that the determination of the accurate CYP2D6 genotype-predicted phenotype is essential in the clinical setting and individualization of drug therapy. The use of the Luminex assay for detection of CYP2D6 polymorphisms could help us more accurately identify an individual's CYP2D6 phenotype.
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Affiliation(s)
- Natchaya Vanwong
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Nattawat Ngamsamut
- Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Thailand
| | - Yaowaluck Hongkaew
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Nopphadol Nuntamool
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand; Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Apichaya Puangpetch
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Montri Chamnanphon
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Ananya Sinrachatanant
- Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Thailand
| | - Penkhae Limsila
- Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
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24
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Karslıoǧlu EH, Özalp E, Çayköylü A. Paliperidone Palmitate-induced Urinary Incontinence: A Case Report. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2016; 14:96-100. [PMID: 26792046 PMCID: PMC4730936 DOI: 10.9758/cpn.2016.14.1.96] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/26/2015] [Accepted: 05/31/2015] [Indexed: 11/25/2022]
Abstract
Urinary incontinence, although rarely reported, is one of the most important adverse effects of antipsychotic medication. It can be an embarrassing, distressing, and potentially treatment-limiting. Several antipsychotics, including both typical and atypical varieties, are known to induce urinary incontinence. Many antipsychotic drugs target the neural pathways controlling continence by binding to receptors of some neurotransmitters such as serotonin, dopamine, acetylcholine, and adrenaline. Pharmacological management of incontinence should be considered if there is a risk of cessation of the antipsychotic therapy or any decline in patients’ compliance. Amitriptyline, desmopressin, ephedrine, and anticholinergics such as oxybutynin and trihexyphenidyl are the most frequently used agents to treat incontinence. We think that the frequency of incontinence is higher than reported in the literature, and that follow-up routines should include a form of standardized screening for all possible adverse effects, including incontinence, of any given antipsychotic. In this article, we report a case of urinary incontinence as an adverse effect of paliperidone palmitate use during maintenance therapy in a patient with schizophrenia.
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Affiliation(s)
- Ersin Hatice Karslıoǧlu
- Department of Psychiatry, T.C.S.B. Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
| | - Elvan Özalp
- Department of Psychiatry, T.C.S.B. Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
| | - Ali Çayköylü
- Department of Psychiatry, T.C.S.B. Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
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25
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Gannon MA, Brown CJ, Stevens RM, Griffith MS, Marczinski CA, Bardgett ME. Early-life risperidone administration alters maternal-offspring interactions and juvenile play fighting. Pharmacol Biochem Behav 2015; 130:90-6. [PMID: 25600754 DOI: 10.1016/j.pbb.2015.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 12/31/2014] [Accepted: 01/09/2015] [Indexed: 01/30/2023]
Abstract
Risperidone is an antipsychotic drug that is approved for use in childhood psychiatric disorders such as autism. One concern regarding the use of this drug in pediatric populations is that it may interfere with social interactions that serve to nurture brain development. This study used rats to assess the impact of risperidone administration on maternal-offspring interactions and juvenile play fighting between cage mates. Mixed-sex litters received daily subcutaneous injections of vehicle or 1.0 or 3.0mg/kg of risperidone between postnatal days (PNDs) 14-42. Rats were weaned and housed three per cage on PND 21. In observations made between PNDs 14-17, risperidone significantly suppressed several aspects of maternal-offspring interactions at 1-hour post-injection. At 23 h post-injection, pups administered risperidone had lower activity scores and made fewer non-nursing contacts with their moms. In observations of play-fighting behavior made once a week between PNDs 22-42, risperidone profoundly decreased many forms of social interaction at 1h post-injection. At 23h post-injection, rats administered risperidone made more non-social contacts with their cage mates, but engaged in less social grooming. Risperidone administration to rats at ages analogous to early childhood through adolescence in humans produces a pattern of abnormal social interactions across the day that could impact how such interactions influence brain development.
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Affiliation(s)
- Matthew A Gannon
- Department of Psychological Science, Northern Kentucky University, United States
| | - Clifford J Brown
- Department of Psychological Science, Northern Kentucky University, United States
| | - Rachel M Stevens
- Department of Psychological Science, Northern Kentucky University, United States
| | - Molly S Griffith
- Department of Psychological Science, Northern Kentucky University, United States
| | - Cecile A Marczinski
- Department of Psychological Science, Northern Kentucky University, United States
| | - Mark E Bardgett
- Department of Psychological Science, Northern Kentucky University, United States.
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26
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Cai S, Lu H, Bai Z, Wu R, Zhao J. Paliperidone extended-release tablets in Chinese patients with schizophrenia: meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat 2015; 11:1817-34. [PMID: 26229477 PMCID: PMC4517523 DOI: 10.2147/ndt.s84833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Previous meta-analyses have compared paliperidone extended-release (ER) tablets with other antipsychotics, but none have involved Chinese patients or studies from People's Republic of China. Further, the results of these meta-analyses may not be applicable to Chinese patients. In the present study, we evaluated the efficacy, safety, and acceptability of paliperidone ER compared with other second-generation antipsychotics (SGAs) for Chinese patients with schizophrenia. METHODS Randomized controlled studies of paliperidone ER and other SGAs as oral monotherapy in the acute phase treatment of schizophrenia were retrieved from Medline, Embase, and the Cochrane Library (CENTRAL), as well as from Chinese databases including the China National Knowledge Infrastructure, Wanfang, and VIP Information/Chinese Scientific Journals Database. We pooled data on response rates, chance of withdrawal due to adverse events, probability of adverse events, and odds of withdrawal for any reason. RESULTS Fifty randomized controlled trials were identified. The response rate for paliperidone ER was significantly higher than that of other pooled SGAs (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.72-0.96) and ziprasidone (RR 0.57, 95% CI 0.39-0.82). Paliperidone ER significantly reduced the chance of withdrawal due to adverse events and the chance of any adverse events compared with other pooled SGAs (RR 0.32, 95% CI 0.17-0.58 and RR 0.88, 95% CI 0.79-0.97) and risperidone (RR 0.31, 95% CI 0.14-0.67 and RR 0.70, 95% CI 0.57-0.86). The incidence of extrapyramidal symptoms on paliperidone ER was comparable with other pooled SGAs (RR 0.94, 95% CI 0.66-1.35) and significantly lower than that of risperidone (RR 0.56, 0.41-0.77) but higher than that of olanzapine (RR 1.88, 95% CI 1.05-3.36). Paliperidone ER was superior to other pooled SGAs (RR 0.32, 95% CI 0.21-0.49 and RR 0.50, 95% CI 0.35-0.72) and olanzapine (RR 0.23, 95% CI 0.15-0.33 and RR 0.33, 95% CI 0.23-0.47) as far as weight gain and somnolence were concerned. Further, prolactin-related adverse events caused by paliperidone ER were comparable with other pooled SGAs (RR 1.30, 95% CI 0.73-2.33), but outnumbered those caused by olanzapine (RR 7.53, 95% CI 2.05-27.71). CONCLUSION Paliperidone ER is efficacious, safe, and well accepted when compared with other pooled SGAs for the treatment of Chinese patients with schizophrenia.
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Affiliation(s)
- Shangli Cai
- Mental Health Institute of the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Hunan, People's Republic of China ; Janssen Research and Development, Beijing, People's Republic of China
| | - Huafei Lu
- Janssen Research and Development, Beijing, People's Republic of China
| | - Zhihua Bai
- Janssen Research and Development, Beijing, People's Republic of China
| | - Renrong Wu
- Mental Health Institute of the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Hunan, People's Republic of China
| | - Jingping Zhao
- Mental Health Institute of the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Hunan, People's Republic of China
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27
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Atypical antipsychotic paliperidone prevents behavioral deficits in mice prenatally challenged with bacterial endotoxin lipopolysaccharide. Eur J Pharmacol 2015; 747:181-9. [DOI: 10.1016/j.ejphar.2014.09.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 09/03/2014] [Accepted: 09/09/2014] [Indexed: 01/25/2023]
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P-glycoprotein activity in the blood–brain barrier is affected by virus-induced neuroinflammation and antipsychotic treatment. Neuropharmacology 2014; 85:548-53. [DOI: 10.1016/j.neuropharm.2014.06.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 06/13/2014] [Accepted: 06/16/2014] [Indexed: 01/16/2023]
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Therapeutic window for striatal dopamine D(2/3) receptor occupancy in older patients with schizophrenia: a pilot PET study. Am J Geriatr Psychiatry 2014; 22:1007-16. [PMID: 25217025 DOI: 10.1016/j.jagp.2013.01.045] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Revised: 01/21/2012] [Accepted: 02/27/2012] [Indexed: 11/23/2022]
Abstract
OBJECTIVE In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D(2/3) receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D(2/3) relative receptor occupancy (RRO) on clinical outcomes in this population. DESIGN Open-label intervention. SETTING Centre for Addiction and Mental Health, Toronto. PARTICIPANTS Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for D(2/3) RRO in dorsal putamen was assessed, using the region of interest analysis of [¹¹C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. RESULTS Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D(2/3) RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D(2/3) RRO. CONCLUSION EPS diminished less than 70% D(2/3) RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.
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Huang Y, Pai C, Cheng K, Kuo W, Chen M, Chang K. Dopamine D2/D3 receptor binding of [123I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging. Nucl Med Biol 2014; 41:681-7. [DOI: 10.1016/j.nucmedbio.2014.04.133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/15/2014] [Accepted: 04/25/2014] [Indexed: 01/03/2023]
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Laffont CM, Gomeni R, Zheng B, Heidbreder C, Fudala PJ, Nasser AF. Population pharmacokinetic modeling and simulation to guide dose selection for RBP-7000, a new sustained-release formulation of risperidone. J Clin Pharmacol 2014; 55:93-103. [DOI: 10.1002/jcph.366] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 07/15/2014] [Indexed: 11/09/2022]
Affiliation(s)
| | | | - Bo Zheng
- Reckitt Benckiser Pharmaceuticals Inc.; Richmond; Virginia VA 23235 USA
| | | | - Paul J. Fudala
- Reckitt Benckiser Pharmaceuticals Inc.; Richmond; Virginia VA 23235 USA
| | - Azmi F. Nasser
- Reckitt Benckiser Pharmaceuticals Inc.; Richmond; Virginia VA 23235 USA
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Andersen CA, Perfetti P, Nibbio M, Bellini M, Angelini R, Fornasier M. Brain penetration assessment in vivo: A reliable and simple method in anesthetized rats at steady state. J Neurosci Methods 2014; 232:199-206. [DOI: 10.1016/j.jneumeth.2014.04.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 03/25/2014] [Accepted: 04/10/2014] [Indexed: 10/25/2022]
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Farrelly LA, Dicker P, Wynne K, English J, Cagney G, Föcking M, Cotter DR. Adolescent Risperidone treatment alters protein expression associated with protein trafficking and cellular metabolism in the adult rat prefrontal cortex. Proteomics 2014; 14:1574-8. [DOI: 10.1002/pmic.201300466] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/24/2014] [Accepted: 03/27/2014] [Indexed: 12/19/2022]
Affiliation(s)
- Lorna A. Farrelly
- Department of Psychiatry; Royal College of Surgeons in Ireland; Education and Research Centre; Beaumont Hospital; Dublin Ireland
| | - Patrick Dicker
- Department of Epidemiology and Public Health; Royal College of Surgeons in Ireland; Dublin Ireland
| | - Kieran Wynne
- School of Biomolecular and Biomedical Research; Conway Institute; University College Dublin; Dublin Ireland
| | - Jane English
- Department of Psychiatry; Royal College of Surgeons in Ireland; Education and Research Centre; Beaumont Hospital; Dublin Ireland
| | - Gerard Cagney
- School of Biomolecular and Biomedical Research; Conway Institute; University College Dublin; Dublin Ireland
| | - Melanie Föcking
- Department of Psychiatry; Royal College of Surgeons in Ireland; Education and Research Centre; Beaumont Hospital; Dublin Ireland
| | - David R. Cotter
- Department of Psychiatry; Royal College of Surgeons in Ireland; Education and Research Centre; Beaumont Hospital; Dublin Ireland
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Yang DS, Seong SJ, Yoon YR, Lim MS, Kwak KH, Lee SJ. Changes in plasma concentrations of risperidone and 9-hydroxyrisperidone and the associated clinical effects during the switch from oral risperidone to extended-release paliperidone tablets in patients with schizophrenia. J Psychopharmacol 2014; 28:341-8. [PMID: 24346811 DOI: 10.1177/0269881113516203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This study aimed to investigate changes in plasma concentrations of risperidone and 9-hydroxy-risperidone (9-OHR) and the associated clinical effects when switching from oral risperidone to extended-release (ER) paliperidone in patients with schizophrenia. This study included 25 patients with schizophrenia. Following a one-week screening period with a stable dose of risperidone, a six-week open-label switch study from risperidone to extended-release paliperidone (paliperidone ER) was conducted. Efficacy and safety assessments were performed on Day 1 and at Weeks 1, 2, 4, and 6. Plasma levels of the active fractions of oral risperidone and paliperidone ER were measured on Day 1 and at Week 1, respectively. Plasma levels of the active moiety (risperidone plus 9-OHR) while taking risperidone (mean dose: 4.0 mg) were significantly higher than plasma levels of 9-OHR while taking 6 mg of paliperidone ER. For 12 subjects taking only 3 mg of risperidone, plasma concentrations of the active moiety of risperidone were also significantly higher than those of 9-OHR while taking 6 mg of paliperidone ER. The amount of reduction in plasma levels was correlated with a temporal deterioration of clinical symptoms. These findings suggest that for patients with schizophrenia taking 3 mg or more of risperidone, an initial switching dose of 6 mg of paliperidone ER may be relatively low in terms of subsequent plasma concentrations and the associated clinical response.
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Affiliation(s)
- Dong Suk Yang
- 1Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, Korea
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Mannheimer B, Holm J, Koukel L, Bertilsson L, Osby U, Eliasson E. Risperidone metabolic ratio as a biomarker of individual CYP2D6 genotype in schizophrenic patients. Eur J Clin Pharmacol 2014; 70:695-9. [PMID: 24643635 DOI: 10.1007/s00228-014-1664-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 02/26/2014] [Indexed: 10/25/2022]
Abstract
PURPOSE The purpose of the present study was to investigate the predictive value of the risperidone metabolic ratio for the individual CYP2D6 genotype. METHODS The determination of risperidone, 9-hydroxyrisperidone, and CYP2D6 genotype was performed in 89 schizophrenic patients. The receiver operator characteristic (ROC) method and the area under the ROC curve (AUC) were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. The area under the ROC curve (AUC) was used as a global measure of this predictive value. To evaluate the proposed cutoff levels of >1 and <0.1 to identify individuals with a poor or ultrarapid CYP2D6 genotype the sensitivity, specificity, positive predictive value and negative predictive were calculated. RESULTS The area under the ROC curve (AUC) for poor and ultrarapid metabolisers was 0.85 and 0.86, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of a risperidone/9-OH-risperidone ratio >1 to CYP2D6 poor metaboliser genotype were 75 %, 95 %, 60 % and 97 %, respectively. The corresponding measures for a metabolic ratio < 0.1 to predict ultrarapid metabolisers were 80 %, 77 %, 18 % and 98 %. CONCLUSIONS A metabolic ratio > 1 or < 0.1 may be a useful therapeutic biomarker to recommend CYP2D6 genetic testing to guide the present or future treatment of patients in need of psychotropic drugs.
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Affiliation(s)
- Buster Mannheimer
- Karolinska Institutet, Department of Clinical Science and Education at Södersjukhuset, Stockholm, Sweden,
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Narasimhan M, Srinivasan S, Pae CU, Masand P. Profile of paliperidone extended release: review of efficacy and safety data. Expert Rev Clin Pharmacol 2014; 1:737-44. [DOI: 10.1586/17512433.1.6.737] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Chue PS, MacKenzie EM, Chue JA, Baker GB. The pharmacology and formulation of paliperidone extended release. Expert Rev Neurother 2014; 12:1399-410. [DOI: 10.1586/ern.12.138] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Low dose risperidone attenuates cue-induced but not heroin-induced reinstatement of heroin seeking in an animal model of relapse. Int J Neuropsychopharmacol 2013; 16:1569-75. [PMID: 23331426 DOI: 10.1017/s1461145712001563] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the effects of pretreatment with risperidone on heroin self-administration and heroin-seeking behaviour induced by cues and heroin priming. Rats were trained to self-administer heroin under a fixed ratio 1 schedule for 2 wk and nose-poke responding was extinguished for 10 d, after which reinstatement of drug seeking was induced by conditioned cues or heroin priming. Acute risperidone administration at doses 10-100 μg/kg potently and dose-dependently inhibited reinstatement of conditioned cue-induced heroin seeking; the minimum dose of inhibition was 30 μg/kg. In contrast, risperidone at the same doses did not attenuate reinstatement induced by two priming doses of heroin (100 or 250 μg/kg s.c.). Risperidone at these doses failed to alter heroin self-administration and locomotion activity. These data demonstrate that acute treatment with low-dose risperidone inhibits conditioned cue-induced heroin seeking and risperidone may be an adjunctive therapy for the treatment of heroin addiction.
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Impact of the ABCB1 gene polymorphism on plasma 9-hydroxyrisperidone and active moiety levels in Japanese patients with schizophrenia. J Clin Psychopharmacol 2013; 33:411-4. [PMID: 23609388 DOI: 10.1097/jcp.0b013e31828ecd52] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C>T, and ABCB1 2677G>T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C>T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C>T genotypes and with age. On the other hand, the ABCB1 2677G>T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C>T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels.
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Miyake N, Miyamoto S, Jarskog LF. New serotonin/dopamine antagonists for the treatment of schizophrenia: are we making real progress? ACTA ACUST UNITED AC 2012; 6:122-33. [PMID: 23006237 DOI: 10.3371/csrp.6.3.4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The introduction of second-generation antipsychotics (SGAs), heralded by clozapine in 1990, represented an important advance in the pharmacologic treatment of schizophrenia. However, several recent comparative effectiveness trials found that non-clozapine SGAs provided little or no advantage in efficacy over first-generation antipsychotics, and all agents had substantial safety and tolerability concerns. Clearly, there remains a great unmet need for more effective and better-tolerated antipsychotics. Relatively potent antagonism of serotonin 5-HT2A receptors coupled with relatively weaker antagonism of dopamine D2 receptors is the central pharmacological characteristic shared by most SGAs. This profile continues to be a favored model for developing new SGAs, commonly defined as serotonin/dopamine antagonists. In the past ten years, aripiprazole, paliperidone, asenapine, iloperidone, and lurasidone have been introduced. Studies suggest that the newer agents have similar short-term efficacy to earlier serotonin/dopamine antagonists, and several demonstrate at least modest improvements in safety and tolerability profiles, particularly metabolic measures. However, as a group, the newer serotonin/dopamine antagonists are pharmacologically heterogeneous, and their side-effect burden can still be considerable. Moreover, their putative clinical advantages have not yet been well demonstrated via direct comparative studies. The absence of such evidence adds to the challenges in defining their place among more established treatment choices, or in providing clinicians with clear indications to guide treatment choices for individual patients. Long-term, head-to-head comparative studies are required to clarify the risk/benefit profiles of the newer antipsychotics and their roles in the treatment of schizophrenia.
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Affiliation(s)
- Nobumi Miyake
- Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, NY, USA
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Wang SM, Han C, Lee SJ, Patkar AA, Pae CU, Fleischhacker WW. Paliperidone: a review of clinical trial data and clinical implications. Clin Drug Investig 2012; 32:497-512. [PMID: 22747259 DOI: 10.2165/11634440-000000000-00000] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Paliperidone, 9-hydroxy-risperidone, is the major metabolite of the atypical antipsychotic risperidone and is available in an oral extended-release (ER) formulation. Paliperidone ER was approved for treating schizophrenia in 2006, and in 2009 it became the first atypical antipsychotic licensed for treating schizoaffective disorder. The short-term efficacy, safety and tolerability of paliperidone ER for patients with schizophrenia were demonstrated in three pivotal 6-week, randomized, double-blind, placebo-controlled studies. Data from the long-term trial showed that paliperidone ER is also effective in preventing relapse of schizophrenia. Two randomized, placebo-controlled, short-term studies have documented the efficacy and tolerability of paliperidone ER in the treatment of schizoaffective disorder, but no long-term or maintenance study has been conducted in patients with schizoaffective disorder. Two 3-week, randomized, double-blind, placebo-controlled studies showed that paliperidone ER is significantly superior to placebo for treating patients with bipolar disorder, but the results were driven by certain subpopulations. Limited evidence suggests that paliperidone ER can potentially be superior to quetiapine and risperidone. However, few direct head-to-head comparisons between paliperidone ER and other antipsychotics have been conducted to confirm these results. The distinctive pharmacological characteristics of paliperidone ER, including smooth fluctuations in plasma drug concentrations, predominantly renal excretion, low risk of causing hepatic impairment and low drug-drug interaction, might provide important clinical advantages compared with risperidone. However, certain side effects require clinical attention. The rate of extrapyramidal side effects was considerably higher than that of a placebo at doses ≥9 mg/day. The risks for orthostatic hypotension, prolongation of the corrected QT interval and hyperprolactinaemia are also concerns. This review summarizes the currently published data on paliperidone ER for treating patients with schizophrenia, schizoaffective disorder and bipolar disorder, and suggests its appropriate use in clinical practice.
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Affiliation(s)
- Sheng-Min Wang
- Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea
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Solid phase microextraction and LC–MS/MS for the determination of paliperidone after stereoselective fungal biotransformation of risperidone. Anal Chim Acta 2012; 742:80-9. [DOI: 10.1016/j.aca.2012.05.056] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 05/25/2012] [Accepted: 05/29/2012] [Indexed: 11/17/2022]
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Risperidone and Total 9-Hydroxyrisperidone in Relation to Prescribed Dose and Other Factors. Ther Drug Monit 2012; 34:349-55. [DOI: 10.1097/ftd.0b013e3182577c43] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Huo R, Tang K, Wei Z, Shen L, Xiong Y, Wu X, Niu J, Han X, Tian Z, Yang L, Feng G, He L, Qin S. Genetic polymorphisms in CYP2E1: association with schizophrenia susceptibility and risperidone response in the Chinese Han population. PLoS One 2012; 7:e34809. [PMID: 22606226 PMCID: PMC3350493 DOI: 10.1371/journal.pone.0034809] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 03/05/2012] [Indexed: 11/18/2022] Open
Abstract
Background CYP2E1 is a member of the cytochrome P450 superfamily, which is involved in the metabolism and activation of both endobiotics and xenobiotics. The genetic polymorphisms of CYP2E1 gene (Chromosome 10q26.3, Accession Number NC_000010.10) are reported to be related to the development of several mental diseases and to be involved in the clinical efficacy of some psychiatric medications. We investigated the possible association of CYP2E1 polymorphisms with susceptibility to schizophrenia in the Chinese Han Population as well as the relationship with response to risperidone in schizophrenia patients. Methods In a case-control study, we identified 11 polymorphisms in the 5' flanking region of CYP2E1 in 228 schizophrenia patients and 384 healthy controls of Chinese Han origin. From among the cases, we chose 130 patients who had undergone 8 weeks of risperidone monotherapy to examine the relationship between their response to risperidone and CYP2E1 polymorphisms. Clinical efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS). Results Statistically significant differences in allele or genotype frequencies were found between cases and controls at rs8192766 (genotype p = 0.0048, permutation p = 0.0483) and rs2070673 (allele: p = 0.0018, permutation p = 0.0199, OR = 1.4528 95%CI = 1.1487–1.8374; genotype: p = 0.0020, permutation p = 0.0225). In addition, a GTCAC haplotype containing 5 SNPs (rs3813867, rs2031920, rs2031921, rs3813870 and rs2031922) was observed to be significantly associated with schizophrenia (p = 7.47E-12, permutation p<0.0001). However, no association was found between CYP2E1 polymorphisms/haplotypes and risperidone response. Conclusions Our results suggest that CYP2E1 may be a potential risk gene for schizophrenia in the Chinese Han population. However, polymorphisms of the CYP2E1 gene may not contribute significantly to individual differences in the therapeutic efficacy of risperidone. Further studies in larger groups are warranted to confirm our results.
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Affiliation(s)
- Ran Huo
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Kefu Tang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Zhiyun Wei
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Lu Shen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Yuyu Xiong
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Xi Wu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Jiamin Niu
- Laiwu Hospital, Shandong, People’s Republic of China
| | - Xia Han
- Laiwu Hospital, Shandong, People’s Republic of China
| | - Zhengan Tian
- Shanghai International Travel Healthcare Center, Shanghai, People’s Republic of China
| | - Lun Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
| | - Guoyin Feng
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
- Shanghai Institute of Mental Health, Shanghai, People’s Republic of China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China
- * E-mail: (HL); (SQ)
| | - Shengying Qin
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Shanghai Genomepilot Institutes, Shanghai, People’s Republic of China
- * E-mail: (HL); (SQ)
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Saar E, Beyer J, Gerostamoulos D, Drummer OH. The analysis of antipsychotic drugs in human matrices using LC-MS(/MS). Drug Test Anal 2012; 4:376-94. [DOI: 10.1002/dta.1337] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 02/17/2012] [Accepted: 02/17/2012] [Indexed: 01/13/2023]
Affiliation(s)
- Eva Saar
- Department of Forensic Medicine; Monash University; Southbank; Victoria; Australia
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Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats. Pharm Res 2012; 29:1932-48. [PMID: 22437487 PMCID: PMC3369128 DOI: 10.1007/s11095-012-0722-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 02/24/2012] [Indexed: 10/29/2022]
Abstract
PURPOSE A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D₂ and serotonin 5-HT(2A) receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats. METHODS A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D₂ and 5-HT(2A) RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D₂ receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT(2A) receptors in the frontal cortex. RESULTS A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D₂ and 5-HT(2A) RO well. Inclusion of binding to 5-HT(2A) receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern. CONCLUSION Binding to both D₂ and 5-HT(2A) receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D₂ and 5-HT(2A) receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.
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Germann D, Kurylo N, Han F. Risperidone. PROFILES OF DRUG SUBSTANCES, EXCIPIENTS, AND RELATED METHODOLOGY 2012; 37:313-61. [PMID: 22469322 DOI: 10.1016/b978-0-12-397220-0.00008-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Dose pattern and effectiveness of paliperidone extended-release tablets in patients with schizophrenia. Clin Neuropharmacol 2012; 34:186-90. [PMID: 21725234 DOI: 10.1097/wnf.0b013e3182281c05] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The objectives of this 12-week multicenter, open-label, noncomparative study were to evaluate the overall effectiveness of paliperidone extended release (ER), the feasibility of maintaining patients on the initial dose of 6 mg, and the relationship between dose pattern and treatment response in schizophrenic patients with inadequate responses to initial treatment in a natural setting. METHODS All patients received 6 mg of paliperidone ER during the first 2 weeks, and subsequently, the dose was adjusted at each visit based on the patient response. We examined the response rate and the effectiveness of different dose patterns of paliperidone ER such as "early increase (dose increased to 9 mg at week 2)," "late increase (dose increased to 9 mg at week 4)," and "maintenance group." RESULTS The response rate based on the Clinical Global Impression of Improvement or Severity response criteria was 33.6% or 61.7%, respectively. The proportion of patients who stayed with the initial dose of 6 mg was 44.5% and the response rate of these patients was 79.8%. When the treatment response to the initial dose of 6 mg is inadequate (Clinical Global Impression of Improvement ≥ 4 at week 2), an early increase in the dose seems to be more effective than maintenance or late increase of the initial dose. CONCLUSIONS This study suggests that paliperidone ER may be an effective and well-tolerated antipsychotics in the treatment of patients with schizophrenia.
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Suzuki Y, Fukui N, Tsuneyama N, Watanabe J, Ono S, Sugai T, Saito M, Inoue Y, Someya T. Effect of the cytochrome P450 2D6*10 allele on risperidone metabolism in Japanese psychiatric patients. Hum Psychopharmacol 2012; 27:43-6. [PMID: 22745940 DOI: 10.1002/hup.1260] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The sum of the serum levels of risperidone (RIS) and 9-hydroxyrisperidone (9-OH-RIS), which is the active moiety serum level, could be important for estimating the clinical effects of RIS. However, there have been no consistent results reported about the relationship between cytochrome P450 (CYP) 2D6*10 allele and plasma 9-OH-RIS or active moiety levels. We investigated the effect of the number of CYP2D6*10 alleles on steady-state plasma RIS, 9-OH-RIS, and active moiety levels in Japanese patients. METHODS Steady-state plasma RIS, 9-OH-RIS, and active moiety levels were measured in 64 patients treated with an average dosage of 4.6 mg/day. RESULTS The number of CYP2D6*10 alleles significantly affected dose-corrected plasma RIS levels (p = 0.001), and the median concentrations in ng/ml/mg were 0.94 (0 allele) vs. 1.73 (1 allele) vs. 3.05 (2 alleles). The number of CYP2D6*10 alleles did not affect plasma 9-OH-RIS or active moiety levels. CONCLUSION The present study shows that the number of CYP2D6*10 alleles affected plasma RIS levels but not plasma 9-OH-RIS and plasma active moiety levels. Because the plasma active moiety levels can influence antipsychotic effects or side effects, the genetic screening of the CYP2D6*10 allele for RIS in Asian populations may not be clinically important.
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Affiliation(s)
- Yutaro Suzuki
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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