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Wu TH, Goh KK, Chiu YH, Lin CH, Chen CH, Lane HY, Lu ML. Inverse dose-dependent effects of aripiprazole on sexual dysfunction and prolactin levels in patients with schizophrenia. J Psychiatr Res 2025; 184:112-117. [PMID: 40049117 DOI: 10.1016/j.jpsychires.2025.02.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 02/10/2025] [Accepted: 02/27/2025] [Indexed: 04/09/2025]
Abstract
Aripiprazole, with its distinct pharmacodynamic profile, acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at 5-HT2A receptors, offering a superior safety profile compared to other antipsychotic drugs. The aim of this study was to assess the dose-dependent effects of aripiprazole on sexual dysfunction and prolactin levels in patients with schizophrenia. Patients receiving aripiprazole were recruited for this study. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS), and sexual dysfunction was evaluated with the Arizona Sexual Experiences Scale (ASEX). Fasting blood samples were collected to measure prolactin levels. A total of 128 patients with schizophrenia were recruited, comprising 86 females and 42 males. The prevalence of hyperprolactinemia, hypoprolactinemia, and sexual dysfunction was 12.5%, 47.6%, and 39.1%, respectively. Patients with sexual dysfunction had significantly higher prolactin levels and a higher prevalence of hyperprolactinemia compared to those without sexual dysfunction. Prolactin levels were significantly correlated with ASEX scores and aripiprazole dose. Multivariate regression analysis revealed that aripiprazole dose and ASEX scores were associated with prolactin levels. Aripiprazole exhibited inverse dose-dependent effects on prolactin levels and ASEX scores in patients with schizophrenia. Prolactin levels were positively correlated with ASEX scores, suggesting an association between prolactin and sexual dysfunction. Both aripiprazole dosing and its effects on prolactin levels may be influenced by sex differences.
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Affiliation(s)
- Tzu-Hua Wu
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Kah Kheng Goh
- Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Hang Chiu
- Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chieh-Hsin Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Hsin Chen
- Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsien-Yuan Lane
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan; Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan
| | - Mong-Liang Lu
- Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Hart XM, Gründer G, Ansermot N, Conca A, Corruble E, Crettol S, Cumming P, Frajerman A, Hefner G, Howes O, Jukic MM, Kim E, Kim S, Maniscalco I, Moriguchi S, Müller DJ, Nakajima S, Osugo M, Paulzen M, Ruhe HG, Scherf-Clavel M, Schoretsanitis G, Serretti A, Spina E, Spigset O, Steimer W, Süzen SH, Uchida H, Unterecker S, Vandenberghe F, Verstuyft C, Zernig G, Hiemke C, Eap CB. Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics. World J Biol Psychiatry 2024; 25:451-536. [PMID: 38913780 DOI: 10.1080/15622975.2024.2366235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 05/12/2024] [Accepted: 06/06/2024] [Indexed: 06/26/2024]
Abstract
BACKGROUND For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.
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Affiliation(s)
- Xenia Marlene Hart
- Department of Molecular Neuroimaging, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Gerhard Gründer
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
- German Center for Mental Health (DZPG), Partner Site Mannheim, Heidelberg, Germany
| | - Nicolas Ansermot
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
| | - Andreas Conca
- Dipartimento di Psichiatria, Comprensorio Sanitario di Bolzano, Bolzano, Italy
| | - Emmanuelle Corruble
- Service Hospitalo-Universitaire de Psychiatrie, Hôpital de Bicêtre, Université Paris-Saclay, AP-HP, Le Kremlin-Bicêtre, France
- Equipe MOODS, Inserm U1018, CESP (Centre de Recherche en Epidémiologie et Sante des Populations), Le Kremlin-Bicêtre, France
| | - Severine Crettol
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
| | - Paul Cumming
- Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland
- School of Psychology and Counseling, Queensland University of Technology, Brisbane, Australia
| | - Ariel Frajerman
- Service Hospitalo-Universitaire de Psychiatrie, Hôpital de Bicêtre, Université Paris-Saclay, AP-HP, Le Kremlin-Bicêtre, France
- Equipe MOODS, Inserm U1018, CESP (Centre de Recherche en Epidémiologie et Sante des Populations), Le Kremlin-Bicêtre, France
| | - Gudrun Hefner
- Forensic Psychiatry, Vitos Clinic for Forensic Psychiatry, Eltville, Germany
| | - Oliver Howes
- Department of Psychosis Studies, IoPPN, King's College London, London, UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, London, UK
| | - Marin M Jukic
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
- Pharmacogenetics Section, Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden
| | - Euitae Kim
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seoyoung Kim
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Ignazio Maniscalco
- Dipartimento di Psichiatria, Comprensorio Sanitario di Bolzano, Bolzano, Italy
| | - Sho Moriguchi
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Daniel J Müller
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Shinichiro Nakajima
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Martin Osugo
- Department of Psychosis Studies, IoPPN, King's College London, London, UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, London, UK
| | - Michael Paulzen
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany
- JARA - Translational Brain Medicine, Alexianer Center for Mental Health, Aachen, Germany
| | - Henricus Gerardus Ruhe
- Department of Psychiatry, Radboudumc, Nijmegen, Netherlands
- Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands
| | - Maike Scherf-Clavel
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
| | - Georgios Schoretsanitis
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | | | - Edoardo Spina
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Olav Spigset
- Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Werner Steimer
- Institute of Clinical Chemistry and Pathobiochemistry, Technical University Munich, Munich, Germany
| | - Sinan H Süzen
- Department of Pharmaceutic Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Hiroyuki Uchida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Stefan Unterecker
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
| | - Frederik Vandenberghe
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
| | - Celine Verstuyft
- Equipe MOODS, Inserm U1018, CESP (Centre de Recherche en Epidémiologie et Sante des Populations), Le Kremlin-Bicêtre, France
- Department of Molecular Genetics, Pharmacogenetics and Hormonology, Bicêtre University Hospital Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Gerald Zernig
- Department of Pharmacology, Medical University Innsbruck, Hall in Tirol, Austria
- Private Practice for Psychotherapy and Court-Certified Witness, Hall in Tirol, Austria
| | - Christoph Hiemke
- Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany
| | - Chin B Eap
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
- Center for Research and Innovation in Clinical Pharmaceutical Sciences, University of Lausanne, Lausanne, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Lausanne, Switzerland
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Liu CI, Liu CM, Chiu HH, Chuang CC, Hwang TJ, Hsieh MH, Chien YL, Lin YT, Yen K, Liu CC. Verification of successful maintenance by serum drug level during a guided antipsychotic reduction to reach minimum effective dose (GARMED) trial. Psychol Med 2024; 54:1-11. [PMID: 39324399 PMCID: PMC11578910 DOI: 10.1017/s0033291724002356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/17/2024] [Accepted: 07/25/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND Inconsistent results regarding the risk of relapse and better subjective outcomes of previous antipsychotic dose reduction trials in patients with remitted psychosis have not been verified using therapeutic drug monitoring (TDM). This study examined plasma drug concentrations of a dose-tapering trial which exhibited the potential of successful maintenance under lower antipsychotic dosages. METHODS A 2-year open-label randomized prospective trial recruited remitted patients to undergo guided antipsychotic tapering. Blood samples were collected at baseline, annually, and after each dose reduction. Plasma aripiprazole/dehydroaripiprazole concentrations were determined using LC-MS/MS. The relationship between the dose and serum drug levels was examined using Spearman's correlation. Divided at 120 ng/mL, relapse rate, global function, quality of life, and psychopathology were compared between high- and low- drug level groups. RESULTS A total of 126 blood samples were collected, after excluding13 samples due of non-adherence. The correlation coefficients between dosage and drug level were 0.853 (aripiprazole) and 0.864 (dehydroaripiprazole), and the dose and concentration plots were parallel along the tapering trajectories, except patients with non-adherence. The concentration-to-dose ratio of aripiprazole in this cohort, 17.79 ± 7.23 ng/mL/mg, was higher than that in Caucasian populations. No significant differences were observed in the clinical outcomes between the high- and low-level groups. Remarkably, 12 of 15 patients maintained remission at plasma aripiprazole concentrations of <120 ng/mL. CONCLUSIONS The lower-than-expected doses reached in our antipsychotic tapering trial were substantiated to provide adequate prophylactic effects by TDM results in a subset of patients treated with aripiprazole, even considering the differences in pharmacogenomics between ethnicities.
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Affiliation(s)
- Chun-I. Liu
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Min Liu
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huai-Hsuan Chiu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Chi Chuang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Tzung-Jeng Hwang
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming H. Hsieh
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ling Chien
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ting Lin
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ko Yen
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Chung Liu
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
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Biso L, Aringhieri S, Carli M, Scarselli M, Longoni B. Therapeutic Drug Monitoring in Psychiatry: Enhancing Treatment Precision and Patient Outcomes. Pharmaceuticals (Basel) 2024; 17:642. [PMID: 38794212 PMCID: PMC11124530 DOI: 10.3390/ph17050642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/09/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
Psychiatric disorders often require pharmacological interventions to alleviate symptoms and improve quality of life. However, achieving an optimal therapeutic outcome is challenging due to several factors, including variability in the individual response, inter-individual differences in drug metabolism, and drug interactions in polytherapy. Therapeutic drug monitoring (TDM), by measuring drug concentrations in biological samples, represents a valuable tool to address these challenges, by tailoring medication regimens to each individual. This review analyzes the current landscape of TDM in psychiatric practice, highlighting its significance in optimizing drug dosages, minimizing adverse effects, and improving therapeutic efficacy. The metabolism of psychiatric medications (i.e., mood stabilizers, antipsychotics, antidepressants) often exhibits significant inter-patient variability. TDM can help address this variability by enhancing treatment personalization, facilitating early suboptimal- or toxic-level detection, and allowing for timely interventions to prevent treatment failure or adverse effects. Furthermore, this review briefly discusses technological advancements and analytical methods supporting the implementation of TDM in psychiatric settings. These innovations enable quick and cost-effective drug concentration measurements, fostering the widespread adoption of TDM as a routine practice in psychiatric care. In conclusion, the integration of TDM in psychiatry can improve treatment outcomes by individualizing medication regimens within the so-called precision medicine.
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Affiliation(s)
- Letizia Biso
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.B.); (M.C.); (M.S.)
| | - Stefano Aringhieri
- Mental Health and Pathological Addiction Department, AUSL Romagna Forlì-Cesena, 47121 Forlì, Italy;
| | - Marco Carli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.B.); (M.C.); (M.S.)
| | - Marco Scarselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.B.); (M.C.); (M.S.)
| | - Biancamaria Longoni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.B.); (M.C.); (M.S.)
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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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Krejčí V, Murínová I, Slanař O, Šíma M. Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics. Prague Med Rep 2024; 125:101-129. [PMID: 38761044 DOI: 10.14712/23362936.2024.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2024] Open
Abstract
Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.
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Affiliation(s)
- Veronika Krejčí
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czech Republic.
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
| | - Irena Murínová
- Department of Applied Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czech Republic
| | - Ondřej Slanař
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Martin Šíma
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Panić B, Jovanović M, Lukić V, Vučićević K, Miljković B, Milovanović S. Association of clozapine and norclozapine levels with patient and therapy characteristics-focus on interaction with valproic acid. Eur J Clin Pharmacol 2023; 79:1557-1564. [PMID: 37733278 DOI: 10.1007/s00228-023-03569-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 09/15/2023] [Indexed: 09/22/2023]
Abstract
PURPOSE The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use. METHODS This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients' data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ. RESULTS A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability. CONCLUSION The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant.
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Affiliation(s)
- Bojana Panić
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Marija Jovanović
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia.
| | - Vera Lukić
- Institute of Forensic Medicine "Milovan Milovanović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Katarina Vučićević
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Branislava Miljković
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Srđan Milovanović
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Clinic for Psychiatry, University Clinical Center of Serbia, Belgrade, Serbia
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Miroshnichenko II, Baymeeva NV, Platova AI, Kaleda VG. [Therapeutic drug monitoring of antipsychotic drugs in routine psychiatric practice]. Zh Nevrol Psikhiatr Im S S Korsakova 2023; 123:145-152. [PMID: 37315254 DOI: 10.17116/jnevro2023123051145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
OBJECTIVE To evaluate the relationship between daily doses of antipsychotic drugs, their serum concentrations, and characteristics of patients treated for schizophrenia or schizophreniform disorder in day-to-day clinical practice. MATERIAL AND METHODS A total of 187 patients were included in the study, 77 (41.1%) patients were on monotherapy, and 110 (58.9%) patients received two or more antipsychotics. Patients age was 27.8±8.1 years, and their body weight was 79.8±15.6 kg. The sample was represented mainly by young men (93.0%). The proportion of smokers was 37.4%. The appropriate HPLC-MS/MS method was used for the simultaneous analysis of 8 antipsychotics and its active metabolites. Serum concentrations of the drugs aripiprazole (ARI), chlorpromazine (CPZ), haloperidol (HAL), zuclopenthixol (ZUC), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), norclozapine (N-desmethylclozapine, NOR), 9-hydroxyrisperidone (9-OH-RIS), dehydroaripiprazole (DGA) were measured. The serum concentration/dose ratio (C/D) was employed as the primary outcome measure, as doses were not kept constant during the study. The active antipsychotic fraction (drug+active metabolite, active moiety - AM) was also evaluated for RIS and ARI. In addition, the metabolite/parent ratio (MPR) was evaluated for RIS and ARI. RESULTS A total of 265 biological samples were obtained, 421 and 203 measurements of the concentration of drugs and their metabolites were carried out, respectively. Overall, 48% of antipsychotics levels were in the expected therapeutic ranges, 30% were below therapeutic ranges, and 22% were above them. A total of 55 patients underwent dose adjustments or drug changes due to ineffectiveness or side-effects. It has been found that smoking reduces the level of C/D for CLO (p<0.01, Mann-Whitney test). We have established that comedication with CLO significantly increases the C/D ratio of QUE (p<0.05, Mann-Whitney test). We have not revealed any influence of weight and age of the subjects on the C/D. The dose-concentration regression relationships are formalized for all AP. CONCLUSION Therapeutical drug monitoring (TDM) is an essential tool to personalize antipsychotic therapy. Careful analysis of TDM data can contribute significantly to the study of the impact of individual patient characteristics on systemic exposure to these drugs.
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Affiliation(s)
| | | | - A I Platova
- Mental Health Research Center, Moscow, Russia
| | - V G Kaleda
- Mental Health Research Center, Moscow, Russia
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Clozapine Blood Concentration Predicts Corrected QT-Interval Prolongation in Patients With Psychoses. J Clin Psychopharmacol 2022; 42:536-543. [PMID: 36356202 DOI: 10.1097/jcp.0000000000001605] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Corrected QT-interval (QTc) prolongation (QTP) is a rare but fatal adverse effect of antipsychotics. Clozapine is the only antipsychotic recommended for treatment of resistant schizophrenia; however, clozapine has been reported to cause QTP. We sought factors predictive of QTP in patients who had antipsychotic polypharmacy involving clozapine. We explored whether the clozapine blood concentration might predict QTP. METHODS We included 133 patients with schizophrenia spectrum disorder who had antipsychotic polypharmacy involving clozapine. We used the χ2 and nonparametric tests to compare clozapine therapeutic drug monitoring (TDM) values and QTc-prolonged person (QTPP) status. Multivariate regression and mediator models were used to identify risk factors for QTPP status and QTP. RESULTS In total, 111 patients were prescribed clozapine. The QTPP rates were 31.3% (20) for men and 23.2% (16) for women. Compared with the non-QTPP group, the QTPP group exhibited significantly higher daily dose of all antipsychotics including clozapine, a higher clozapine dose, and elevated clozapine and norclozapine TDM values. Furthermore, such patients were prescribed a greater number of antipsychotics. Multivariate logistic regression revealed that only the clozapine TDM value could be predictive factor for QTPP status (P = 0.018). A clozapine TDM value above the therapeutic range (>600 mg/dL) was associated with a high risk of QTPP status (adjusted odds ratio, 6.5; 95% confidence interval, 1.7-25.2; P = 0.006). The mediator model revealed that the clozapine TDM values completely mediated the association between the clozapine dose and the QTc interval. CONCLUSIONS The clozapine blood concentration reliably predicts QTP in patients with clozapine use.
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Bernardo M, Mezquida G, Ferré P, Cabrera B, Torra M, Lizana AM, Brunet M. Dried Blood Spot (DBS) as a useful tool to improve clozapine, aripiprazole and paliperidone treatment: From adherence to efficiency. REVISTA DE PSIQUIATRIA Y SALUD MENTAL 2022; 15:230-237. [PMID: 36513399 DOI: 10.1016/j.rpsmen.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/18/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety. METHODS 31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25μl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma. RESULTS Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (r2, from 0.500 to 0.721). The correlation between conventional plasma and DBS concentrations for paliperidone, aripiprazole, clozapine, and their metabolites were moderate, suggesting that optimal drug target concentrations should be established for DBS. CONCLUSIONS In this study, for aripiprazole, dehydroaripiprazole, paliperidone, clozapine and desmethylclozapine, DBS has provided good analytical performance for TDM. Thus, DBS sampling can offer a great alternative over conventional sampling for plasma measurement. The assay provides good analytical performances for TDM and clinical research applicability, suggesting that DBS is a promising clinical application in TDM in psychiatry.
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Affiliation(s)
- Miguel Bernardo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute, Department of Medicine, University of Barcelona, Biomedical Research Networking Center for Mental Health Network (CIBERSAM), August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Gisela Mezquida
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute; Department of Basic Clinal Practice, Pharmacology Unit, University of Barcelona, Biomedical Research Networking Center for Mental Health Network (CIBERSAM), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Paula Ferré
- Pharmacology and Toxicology Laboratoy, SBGM, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Bibiana Cabrera
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute, Department of Medicine, University of Barcelona, Biomedical Research Networking Center for Mental Health Network (CIBERSAM), August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Mercè Torra
- Pharmacology and Toxicology Laboratoy, SBGM, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Ana Maria Lizana
- Pharmacology and Toxicology Laboratoy, SBGM, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, SBGM, Hospital Clínic of Barcelona, Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain.
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11
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Dried Blood Spot (DBS) as a useful tool to improve clozapine, aripiprazole and paliperidone treatment: from adherence to efficiency. REVISTA DE PSIQUIATRIA Y SALUD MENTAL 2022. [DOI: 10.1016/j.rpsm.2022.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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12
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Tien Y, Huang HP, Liao DL, Huang SC. Dose-response analysis of aripiprazole in patients with schizophrenia in Taiwan. Ther Adv Psychopharmacol 2022; 12:20451253221113238. [PMID: 35923249 PMCID: PMC9340887 DOI: 10.1177/20451253221113238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/26/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Aripiprazole is a third-generation antipsychotic agent with acceptable efficacy and a good safety profile. Previous studies have indicated the therapeutic serum concentration of aripiprazole to be 100 to 350 ng/ml; however, most of these studies examined a Western population. Patients with schizophrenia from Tungs' Taichung MetroHarbor Hospital in central Taiwan were recruited to analyze the dose-response relationship of aripiprazole in the Chinese population. OBJECTIVE We aimed to investigate whether a serum concentration of aripiprazole higher than the current suggested range leads to higher response rates. DESIGN A prospective cohort study was designed to investigate the response rates in different studied cohorts grouped by serum concentration of aripiprazole. DATA SOURCES AND METHODS Data of 64 patients who presented to a single medical center in central Taiwan and who received therapeutic drug monitoring (TDM) were obtained. Serum concentrations of aripiprazole were correlated with the clinical response of patients by using the Clinical Global Impressions (CGI) scores. RESULTS The mean concentration of aripiprazole was 432.1 ± 275.1 ng/ml in the study cohort. Among the much-improved patients, the mean serum concentration of aripiprazole was 494 ± 273 ng/ml (25th-75th percentiles 264-666 ng/ml), which was higher than the current recommended therapeutic target of 100-350 ng/ml for aripiprazole. The response rate in the severe group (baseline CGI score of 6 or 7) was significantly higher than in the moderate group (baseline CGI score of 4 or 5; 86.7% versus 55.9%, p = 0.007). CONCLUSION A significantly higher response rate was observed in the study cohort with serum aripiprazole concentrations over 300 ng/ml. Therefore, dosing higher than the current recommended range may potentially improve the treatment efficacy in the Chinese population. Because the serum concentration varies among patients due to multiple intrinsic and extrinsic factors, TDM, especially in outpatients, is recommended if the clinical response is limited.
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Affiliation(s)
- Yun Tien
- Department of Psychiatry, Taoyuan Psychiatric Center, Taoyuan City, Taiwan (ROC)
| | - Hsiang-Ping Huang
- Department of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Rd., Guishan Dist., Taoyuan City 33303, Taiwan (ROC)
| | - Ding-Lieh Liao
- Department of Psychiatry, Bali Psychiatric Center, New Taipei City, Taiwan (ROC)
| | - Shang-Chien Huang
- Department of Psychiatry, Tungs' Taichung MetroHarbor Hospital, No. 699, Section 8, Taiwan Boulevard, Wuqi District, Taichung City 43503, Taiwan (ROC)
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Mercolini L. Editorial: Advances in therapeutic drug monitoring of psychiatric subjects: Analytical strategies and clinical approaches. Front Psychiatry 2022; 13:1056380. [PMID: 36329918 PMCID: PMC9623277 DOI: 10.3389/fpsyt.2022.1056380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/04/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Laura Mercolini
- Research Group of Pharmaco-Toxicological Analysis (PTA Lab), Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum-University of Bologna, Bologna, Italy
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Zidekova N, Nemcek A, Sutovska M, Mokry J, Kertys M. Development of Sensitive and High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Method for Quantification of Haloperidol in Human Plasma with Phospholipid Removal Pretreatment. J Anal Toxicol 2021; 45:573-580. [PMID: 32886781 DOI: 10.1093/jat/bkaa124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/17/2020] [Accepted: 09/01/2020] [Indexed: 11/13/2022] Open
Abstract
Haloperidol, butyrophenone derivative, is a typical antipsychotic drug used in the treatment of schizophrenia, manic phase of bipolar disorder, and acute psychomotor agitations. According to the recent guidelines for therapeutic drug monitoring, it is strongly recommended to measure plasma level during the therapy with haloperidol. The objective of this study was to develop and validate a simple liquid chromatography-tandem mass spectrometry-based method to quantitate haloperidol in human plasma. After one-step extraction procedure using OSTROTM plate, gradient elution on Acquity UPLC BEH C18 (50 ×2.1mm, 1.7μm) column over 3.2 min was performed. The detection was conducted on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode in positive ionization mode with transitions at m/z 376.29 → 165.14 and m/z 380.28 → 169.17 for haloperidol and haloperidol-d4 (used as an internal standard), respectively. The method was fully validated to cover wide concentration range of 0.05-80 ng/mL in human plasma and meets the criteria for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability. The extraction recovery was nearly 100%, and no significant matrix effects were observed. Therefore, the method is applicable to routine therapeutic drug monitoring in patients' plasma.
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Affiliation(s)
- Nela Zidekova
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - Adam Nemcek
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia.,Faculty Hospital with Polyclinic, Nove Zamky, Slovakia
| | - Martina Sutovska
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - Juraj Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - Martin Kertys
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
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Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, Fasciani I, Annibale P, Maggio R, Scarselli M. Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences. Pharmaceuticals (Basel) 2021; 14:238. [PMID: 33800403 PMCID: PMC8001502 DOI: 10.3390/ph14030238] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5'AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP's higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.
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Affiliation(s)
- Marco Carli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Shivakumar Kolachalam
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Biancamaria Longoni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Anna Pintaudi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Marco Baldini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Stefano Aringhieri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Irene Fasciani
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (I.F.); (R.M.)
| | - Paolo Annibale
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
| | - Roberto Maggio
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (I.F.); (R.M.)
| | - Marco Scarselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
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16
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Qi Y, Liu G. Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Simultaneous Determination of Antipsychotic Drugs in Human Plasma and Its Application in Therapeutic Drug Monitoring. Drug Des Devel Ther 2021; 15:463-479. [PMID: 33613026 PMCID: PMC7887337 DOI: 10.2147/dddt.s290963] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/21/2021] [Indexed: 01/22/2023] Open
Abstract
PURPOSE We developed and validated an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous therapeutic drug monitoring (TDM) and clinical pharmacokinetic antipsychotic drugs: clozapine (CLP), chlorpromazine (CPZ), risperidone (RPD), paliperidone (PLD), quetiapine (QTP;), aripiprazole (APZ), dehydroaripiprazole (DAP), olanzapine (OZP), ziprasidone (ZRD), and amisulpride (ASP). METHODS Analytes and internal standards (ISs) were separated using a Phenomenex phenyl-hexyl column (50.0 × 2.1 mm, 1.7 μm) with water containing 0.1% formic acid and 2 mM ammonium acetate, and methanol containing 0.1% formic acid and 2 mM ammonium acetate as the mobile phase. The antipsychotic drugs and ISs were extracted from 50 μL of plasma using acetonitrile. RESULTS The calibration ranges were 25.0-1500.0 ng/mL for CLP, CPZ, DAP, and QTP, 10.0-600.0 ng/mL for CPZ and ZRD, 2.5-150.0 ng/mL for RPD, 5.0-300.0 ng/mL for PLD and OZP, and 20.0-1200.0 ng/mL for ASP. Validation was carried out according to the guidelines for bioanalytical validation, including assessment of calibration curves, specificity, accuracy, precision, recovery, stability, dilution integrity, and matrix effect. All the results satisfied the requirements. CONCLUSION The results provided significant information to support future clinical TDM and rational drug use research. The proposed method also provided a simple, reliable, specific, and suitable technique for TDM and pharmacokinetic studies.
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Affiliation(s)
- Yingjie Qi
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, Liaoning Province, People’s Republic of China
| | - Guangxuan Liu
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, Liaoning Province, People’s Republic of China
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Šálek T, Schneiderka P, Studená B, Votroubková M. Survey on request form content and result reporting in therapeutic drug monitoring service among laboratories in Czechia and Slovakia. Biochem Med (Zagreb) 2021; 30:020706. [PMID: 32550814 PMCID: PMC7271755 DOI: 10.11613/bm.2020.020706] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/12/2020] [Indexed: 01/06/2023] Open
Abstract
Introduction The aim of the study was to investigate current practice and policies of therapeutic drug monitoring (TDM) service requesting and result reporting in Czechia and Slovakia. Materials and methods All 149 laboratories that measure plasma drug concentrations were given an online questionnaire during a regular external quality assessment TDM cycle. The questionnaire consisted of 17 questions. The optimal TDM practice was defined as the application of all elements (age, body weight, time of sampling, date of the first administration, time of the last dose administration, the dose, the dosing interval, the route of administration, information on reason of testing, and information on other co–administered drugs) needed for reporting a recommendation for further drug dosing (positive response to question number 16). Results The response rate was 69%, 103 out of 149 laboratories measuring drug concentrations. Only 12% (12 out of 103 laboratories) of the laboratories implemented all elements needed for optimal TDM practice and reported a recommendation. Both paper and electronic request forms were used by 77 out of 103 (75%) laboratories. A total of 69 out of 103 laboratories (67%) specified the type of sampling tube on their request form. Cystatin C was used for prediction of renal drug elimination by 24% (25 out of 103) of participants. Conclusions Small number of laboratories implemented all elements needed for optimal TDM practice and report a recommendation on further dosing. Further efforts in education on optimal TDM practice as well as harmonization of service are desirable.
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Affiliation(s)
- Tomáš Šálek
- Department of Clinical Biochemistry and Pharmacology, Tomas Bata Hospital, Zlín, Czech Republic
| | | | - Barbora Studená
- Institute of Clinical Biochemistry and Diagnostics, Medical Faculty in Hradec Králové, Charles University, Prague, Czech Republic
| | - Michaela Votroubková
- Institute of Environmental and Chemical Engineering, University of Pardubice, Czech Republic
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Campêlo JDM, Rodrigues TB, Costa JL, Santos JM. Optimization of QuEChERS extraction for detection and quantification of 20 antidepressants in postmortem blood samples by LC-MS/MS. Forensic Sci Int 2020; 319:110660. [PMID: 33385954 DOI: 10.1016/j.forsciint.2020.110660] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 11/29/2022]
Abstract
In this study, a comprehensively optimization of QuEChERS (quick, easy, cheap, effective, rugged and safe) method using design of experiments (DOE) was conducted to evaluate the best conditions to obtain the most effective extraction. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis was performed to identify and quantify the antidepressants, with electrospray ionization acquired in positive mode. The method was validated for all analytes; the calibration curves were linear from 10-1000ng/mL, with R2>0.98, and with LOD and LOQ defined as 10ng/mL. Method imprecision and bias were less than 14.3% and 18.9%, respectively. Neither carryover nor interferences were observed. Overall, the optimized method was applied in postmortem real sample analysis to quantify the antidepressants. This study showed a viable method that can be applied for routine forensic analysis, with a quick and easy sample preparation and a rapid total run time of 8min for each analysis.
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Affiliation(s)
- Jacqueline de M Campêlo
- Chemistry Department, Federal Rural University of Pernambuco, UFRPE, Recife, Pernambuco, Brazil
| | - Taís B Rodrigues
- Campinas Poison Control Center, Faculty of Medical Sciences, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Jose L Costa
- Campinas Poison Control Center, Faculty of Medical Sciences, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil; Faculty of Pharmaceutical Sciences, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Jandyson M Santos
- Chemistry Department, Federal Rural University of Pernambuco, UFRPE, Recife, Pernambuco, Brazil.
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Proença P, Monteiro C, Mustra C, Claro A, Franco J, Corte-Real F. Identification and Quantification of Antipsychotics in Blood Samples by LC-MS-MS: Case Reports and Data from Three Years of Routine Analysis. J Anal Toxicol 2020; 44:915-922. [PMID: 32780823 DOI: 10.1093/jat/bkaa100] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 07/21/2020] [Accepted: 08/03/2020] [Indexed: 11/14/2022] Open
Abstract
Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.
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Affiliation(s)
- Paula Proença
- Instituto Nacional de Medicina Legal e Ciências Forenses, I.P., Delegação do Centro, Coimbra, Portugal
| | - Carla Monteiro
- Instituto Nacional de Medicina Legal e Ciências Forenses, I.P., Delegação do Centro, Coimbra, Portugal
| | - Carla Mustra
- Instituto Nacional de Medicina Legal e Ciências Forenses, I.P., Delegação do Centro, Coimbra, Portugal
| | - Alda Claro
- Instituto Nacional de Medicina Legal e Ciências Forenses, I.P., Delegação do Centro, Coimbra, Portugal
| | - João Franco
- Instituto Nacional de Medicina Legal e Ciências Forenses, I.P., Delegação do Sul, Lisboa, Portugal
| | - Francisco Corte-Real
- Instituto Nacional de Medicina Legal e Ciências Forenses, I.P., Delegação do Centro, Coimbra, Portugal.,Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
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Shukla RP, Rapier C, Glassman M, Liu F, Kelly DL, Ben-Yoav H. An integrated electrochemical microsystem for real-time treatment monitoring of clozapine in microliter volume samples from schizophrenia patients. Electrochem commun 2020. [DOI: 10.1016/j.elecom.2020.106850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Electromembrane extraction of chlorprothixene, haloperidol and risperidone from whole blood and urine. J Chromatogr A 2020; 1629:461480. [DOI: 10.1016/j.chroma.2020.461480] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 01/30/2023]
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Assessment of Antiepileptic Drug Concentrations in HIV-Infected versus HIV-Negative Patients: A Retrospective Analysis. Clin Pharmacokinet 2020; 58:1345-1350. [PMID: 30945117 DOI: 10.1007/s40262-019-00752-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION A higher rate of subtherapeutic psychotropic drug concentrations was recently found in HIV-infected versus HIV-negative patients. In this study, we sought to investigate if this trend could also apply to antiepileptic drugs. METHODS Overall, 700 HIV-infected patients were screened during the first 2 years after the introduction of our outpatient polytherapy management service (Gestione Ambulatoriale Politerapie [GAP]) in the search for subjects with antiepileptic drug trough concentration assessments. The distribution of such concentrations was compared with that in HIV-negative patients monitored over the same period. RESULTS The search identified 97 HIV-infected patients concomitantly receiving antiretroviral and antiepileptic drugs, for a total of 310 drug measurements. Overall, 30%, 64% and 6%, versus 28%, 65% and 7%, of the antiepileptic concentrations measured in HIV-infected versus HIV-negative patients (1090 patients, for a total of 3488 antiepileptic concentrations measured) were below, within, or above the therapeutic targets, respectively. The antiepileptic drug valproate was associated with the highest risk of subtherapeutic drug concentrations, with 57% and 46% of determinations below the therapeutic range in HIV-positive and HIV-negative patients, respectively. Remarkably, the concentrations of valproate were significantly lower in HIV-infected versus HIV-negative patients (47.9 ± 21.2 versus 53.9 ± 21.6 mg/L; p < 0.05). CONCLUSION In our retrospective study, most HIV-infected patients had antiepileptic drug concentrations falling within the therapeutic targets, with the exception of valproate, which was associated with a higher rate of subtherapeutic concentrations compared with other antiepileptic drugs.
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Tanna S, Ogwu J, Lawson G. Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives. ACTA ACUST UNITED AC 2020; 58:643-663. [DOI: 10.1515/cclm-2019-0820] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/19/2019] [Indexed: 11/15/2022]
Abstract
AbstractNonadherence to prescribed pharmacotherapy is an understated public health problem globally and is costing many patients their chance to return to good health and healthcare systems billions. Clinicians need an accurate assessment of adherence to medications to aid the clinical decision-making process in the event of poor patient progress and to maximise the patient health outcomes from the drug therapies prescribed. An overview of indirect and direct methods used to measure medication adherence is presented, highlighting the potential for accurate measuring of drugs in biological samples using hyphenated mass spectrometry (MS) techniques to provide healthcare professionals with a reliable evidence base for clinical decision making. In this review we summarise published applications of hyphenated MS techniques for a diverse range of clinical areas demonstrating the rise in the use of such direct methods for assessing medication adherence. Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods using plasma, serum and urine samples are the most popular, in recent years increased attention has been given to liquid chromatography high-resolution mass spectrometry (LC-HRMS) methods and alternative biosample matrices including hair, saliva and blood microsamples. The advantages and challenges of using hyphenated MS techniques to address this healthcare problem are also discussed alongside future perspectives.
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Affiliation(s)
- Sangeeta Tanna
- Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, UK
| | - John Ogwu
- Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, UK
| | - Graham Lawson
- Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, UK
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Kamil Gharab KM, Onmaz DE, Abusoglu S, Aydin M, Sivrikaya A, Tok O, Abusoglu G, Unlu A. The relationship between serum clozapine concentrations and hematological parameters by a validated mass spectrometric method. J Pharm Biomed Anal 2020; 180:113056. [PMID: 31887669 DOI: 10.1016/j.jpba.2019.113056] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/10/2019] [Accepted: 12/18/2019] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Clozapine is one of the most effective drugs for resistant schizophrenia, but its severe metabolic and hematological side effects limit the use of clozapine. It has been reported that clozapine blood concentrations should be maintained between 350-600 ng/mL. Our aim was to develop a determination method for clozapine and its main metabolites norclozapine and clozapine-N-oxide, to perform validation studies and to investigate the change of various biochemical parameters in patients using clozapine. METHODS A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for clozapine measurement. Thus, blood samples were collected from 38 patients with schizophrenia and 32 healthy volunteers. Biochemical and hematological parameters were measured by Beckman-Coulter AU 5800 (Beckman Coulter, Brea, USA) and Beckman Coulter LH 780 analyzer (Beckman Coulter, Miami, FL, USA), respectively. Hormone levels were analyzed using Cobas 6000 analyzer (Roche Diagnostics, Germany). RESULTS The LCMS/MS method was linear between 1.22-2500 ng/mL (r2 = 0.9971) for clozapine. The retention times of clozapine, norclozapine and clozapine-N-oxide were 0.92, 0.89 and 0.95, respectively. Blood glucose (GLU) (p = 0.025), low density lipoprotein (LDL-cholesterol) (p = 0.015), triglyseride (TG) (p = 0.042) and total cholesterol (TC) (p = 0.024) levels were higher; hemoglobin (HGB) (0.015), mean corpuscular hemoglobin (MCH) (0.036), red blood cell count (RBC) (0.020), neutrophil (NEU) (0.034), and platelet (PLT) (P = 0.005) levels were lower in the clozapine group. CONCLUSIONS This LC-MS/MS method was rapid, simple, cost-effective and suitable for the routine clozapine monitoring. Furthermore, norclozapine and clozapine-N-oxide were also determined. Monitoring of metabolic and hematological parameters with clozapine levels is very important. However, the limitations of the study were that the method was not validated for norclozapine and clozapine-N-oxide, so the validation parameters were not evaluated for these two metabolites.
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Affiliation(s)
| | - Duygu Eryavuz Onmaz
- Department of Biochemistry, Selcuk University, Faculty of Medicine, Konya, Turkey.
| | - Sedat Abusoglu
- Department of Biochemistry, Selcuk University, Faculty of Medicine, Konya, Turkey
| | - Memduha Aydin
- Department of Psychiatry, Selcuk University, Faculty of Medicine, Konya, Turkey
| | - Abdullah Sivrikaya
- Department of Biochemistry, Selcuk University, Faculty of Medicine, Konya, Turkey
| | - Oguzhan Tok
- Department of Biochemistry, Selcuk University, Faculty of Medicine, Konya, Turkey
| | - Gulsum Abusoglu
- Department of Medical Laboratory Techniques, Selcuk University, Vocational School of Health, Konya, Turkey
| | - Ali Unlu
- Department of Biochemistry, Selcuk University, Faculty of Medicine, Konya, Turkey
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Jovanović M, Vučićević K, Miljković B. Understanding variability in the pharmacokinetics of atypical antipsychotics - focus on clozapine, olanzapine and aripiprazole population models. Drug Metab Rev 2020; 52:1-18. [PMID: 32008418 DOI: 10.1080/03602532.2020.1717517] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Antipsychotic medicines are widely used for the management of psychotic symptoms regardless of the underlying diagnosis. Most atypical antipsychotics undergo extensive metabolism prior to excretion. Various factors may influence their pharmacokinetics, particularly elimination, leading to highly variable drug concentrations between individual patients following the same dosing regimen. Population pharmacokinetic approach, based on nonlinear mixed effects modeling, is a useful tool to identify covariates explaining pharmacokinetic variability, as well as to characterize and distinguish unexplained residual and between-subject (interindividual) variability. In addition, this approach allows the use of both sparsely and intensively sampled data. In this paper, we reviewed the pharmacokinetic characteristics of clozapine, olanzapine and aripiprazole, focusing on a population modeling approach. In particular, models based on a nonlinear mixed effects approach performed by NONMEM® software in order to identify and quantify sources of pharmacokinetic variability are presented. Population models were identified through systematic searches of PubMed and sixteen studies were selected. Some of the factors identified that significantly contribute to variability in elimination among clozapine, olanzapine, and aripiprazole are demographic characteristics, body weight, genetic polymorphism, smoking and in some cases drug interactions. Scientific research based on pharmacometric modeling is useful to further characterize sources of variability and their combined effect.
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Affiliation(s)
- Marija Jovanović
- Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Republic of Serbia
| | - Katarina Vučićević
- Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Republic of Serbia
| | - Branislava Miljković
- Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Republic of Serbia
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Shukla RP, Ben‐Yoav H. A Chitosan-Carbon Nanotube-Modified Microelectrode for In Situ Detection of Blood Levels of the Antipsychotic Clozapine in a Finger-Pricked Sample Volume. Adv Healthc Mater 2019; 8:e1900462. [PMID: 31240866 DOI: 10.1002/adhm.201900462] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/07/2019] [Indexed: 01/06/2023]
Abstract
The antipsychotic clozapine is the most effective medication available for schizophrenia and it is the only antipsychotic with a known efficacious clinical range. However, it is dramatically underutilized due to the inability to test clozapine blood levels in finger-pricked patients' samples. This prevents obtaining immediate blood levels information, resulting in suboptimal treatment. The development of an electrochemical microsensor is presented, which enables, for the first time, clozapine detection in microliters volume whole blood. The sensor is based on a microelectrode modified with micrometer-thick biopolymer chitosan encapsulating carbon nanotubes. The developed sensor detects clozapine oxidation current, in the presence of other electroactive species in the blood, which generate overlapping electrochemical signals. Clozapine detection, characterized in whole blood from healthy volunteers, displays a sensitivity of 32 ± 3.0 µA cm-2 µmol-1 L and a limit-of-detection of 0.5 ± 0.03 µmol L-1 . Finally, the developed sensor displays a reproducible electrochemical signal (0.6% relative standard deviation) and high storage stability (9.8% relative standard deviation after 8 days) in serum samples and high repeatability (9% relative standard deviation for the 5th repetition) in whole blood samples. By enabling the rapid and minimally invasive clozapine detection at the point-of-care, an optimal schizophrenia treatment is provided.
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Affiliation(s)
- Rajendra P. Shukla
- Nanobioelectronics LaboratoryDepartment of Biomedical EngineeringBen‐Gurion University of the Negev Beer‐Sheva 8410501 Israel
| | - Hadar Ben‐Yoav
- Nanobioelectronics LaboratoryDepartment of Biomedical EngineeringBen‐Gurion University of the Negev Beer‐Sheva 8410501 Israel
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Pardiñas AF, Nalmpanti M, Pocklington AJ, Legge SE, Medway C, King A, Jansen J, Helthuis M, Zammit S, MacCabe J, Owen MJ, O'Donovan MC, Walters JTR. Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism. Am J Psychiatry 2019; 176:477-486. [PMID: 30922102 DOI: 10.1176/appi.ajp.2019.18050589] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. METHODS The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. RESULTS The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. CONCLUSIONS Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.
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Affiliation(s)
- Antonio F Pardiñas
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Mariana Nalmpanti
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Andrew J Pocklington
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Sophie E Legge
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Christopher Medway
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Adrian King
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - John Jansen
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Marinka Helthuis
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Stanley Zammit
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - James MacCabe
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Michael J Owen
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - Michael C O'Donovan
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
| | - James T R Walters
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe)
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Bába LI, Kolcsár M, Kun IZ, Ulakcsai Z, Bagaméry F, Szökő É, Tábi T, Gáll Z. Effects of Cariprazine, Aripiprazole, and Olanzapine on Mouse Fibroblast Culture: Changes in Adiponectin Contents in Supernatants, Triglyceride Accumulation, and Peroxisome Proliferator-Activated Receptor-γ Expression. ACTA ACUST UNITED AC 2019; 55:medicina55050160. [PMID: 31108997 PMCID: PMC6571602 DOI: 10.3390/medicina55050160] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 05/05/2019] [Accepted: 05/14/2019] [Indexed: 02/01/2023]
Abstract
Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose–tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 µg/mL), OLA (1 and 20 µg/mL), and CAR (0.1 and 2 µg/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p < 0.05). Although PPAR-γ levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-γ expression (p < 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-γ expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect.
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Affiliation(s)
- László-István Bába
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Tîrgu Mureș, 540139 Tîrgu Mureș, Romania.
| | - Melinda Kolcsár
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Tîrgu Mureș, 540139 Tîrgu Mureș, Romania.
| | - Imre Zoltán Kun
- Doctoral School, Faculty of Medicine, University of Medicine, Pharmacy, Sciences and Technology of Tîrgu Mureș, 540139 Tîrgu Mureș, Romania.
| | - Zsófia Ulakcsai
- Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Hungary.
| | - Fruzsina Bagaméry
- Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Hungary.
| | - Éva Szökő
- Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Hungary.
| | - Tamás Tábi
- Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Hungary.
| | - Zsolt Gáll
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Tîrgu Mureș, 540139 Tîrgu Mureș, Romania.
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Baymeeva NV, Platova AI, Kaleda VG, Miroshnichenko II. [Therapeutic drug monitoring of risperidone and its active metabolite 9-hydroxyrisperidone in the treatment of schizophrenia]. Zh Nevrol Psikhiatr Im S S Korsakova 2019; 119:24-28. [PMID: 31089091 DOI: 10.17116/jnevro201911903124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIM To conduct a routine therapeutic drug monitoring (TDM) and analyze its results for the optimization of pharmacotherapy. MATERIAL AND METHODS Fifty-six inpatients (in total 68 samples) with various forms of schizophrenia were enrolled. High performance liquid chromatography with mass-spectrometric detection was used for quantitative determination of risperidone and 9-hydroxyrisperidone in the serum. RESULTS Concentrations of risperidone and 9-hydroxyrisperidone were correlated with drug dose. Total concentrations in the blood at doses from 2 to 8 mg per day were distributed as follows: 44.1% were in the therapeutic, 29.4% in sub-therapeutic (<20 ng/mL) and 26.5% in conditionally toxic range (>60 ng/mL). CONCLUSIONS Concentrations of risperidone and 9-hydroxyrisperidone did not follow the normal distribution. The results showed that monitoring of the total concentration of risperidone and its metabolite 9-hydroxyrisperidone was an effective tool for testing and quality control for the purpose of individualization of pharmacotherapy.
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Affiliation(s)
| | - A I Platova
- Mental Health Research Center, Moscow, Russia
| | - V G Kaleda
- Mental Health Research Center, Moscow, Russia
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Wong YC, Centanni M, de Lange ECM. Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human. J Clin Pharmacol 2019; 59:731-747. [PMID: 30676661 PMCID: PMC6590357 DOI: 10.1002/jcph.1365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 11/24/2018] [Indexed: 12/17/2022]
Abstract
Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK‐Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood‐brain barrier parameters including the expression and efflux transport kinetics of P‐glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model. Based on the simulated drug and metabolite concentrations in brainECF, drug‐D2 receptor binding kinetics (association and dissociation rates) were incorporated in MoBi to predict RO. From an extensive literature search, 32 plasma PK data sets (16 from rat and 16 from human studies) and 23 striatum RO data sets (13 from rat and 10 from human studies) were prepared and compared with the model predictions. The rat PBPK‐RO model adequately predicted the plasma concentrations of the parent drugs and metabolites and the RO levels. The human PBPK‐RO model also captured the plasma PK and RO levels despite the large interindividual and interstudy variability, although it tended to underestimate the plasma concentrations and RO measured at late time points after risperidone dosing. The developed human PBPK‐RO model was successfully applied to predict the plasma PK and RO changes observed after risperidone dose reduction in a clinical trial in schizophrenic patients.
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Affiliation(s)
- Yin Cheong Wong
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Maddalena Centanni
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Elizabeth C M de Lange
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
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31
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Balashova EE, Maslov DL, Lokhov PG. A Metabolomics Approach to Pharmacotherapy Personalization. J Pers Med 2018; 8:jpm8030028. [PMID: 30189667 PMCID: PMC6164342 DOI: 10.3390/jpm8030028] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 08/17/2018] [Accepted: 09/03/2018] [Indexed: 12/27/2022] Open
Abstract
The optimization of drug therapy according to the personal characteristics of patients is a perspective direction in modern medicine. One of the possible ways to achieve such personalization is through the application of "omics" technologies, including current, promising metabolomics methods. This review demonstrates that the analysis of pre-dose metabolite biofluid profiles allows clinicians to predict the effectiveness of a selected drug treatment for a given individual. In the review, it is also shown that the monitoring of post-dose metabolite profiles could allow clinicians to evaluate drug efficiency, the reaction of the host to the treatment, and the outcome of the therapy. A comparative description of pharmacotherapy personalization (pharmacogenomics, pharmacoproteomics, and therapeutic drug monitoring) and personalization based on the analysis of metabolite profiles for biofluids (pharmacometabolomics) is also provided.
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Affiliation(s)
- Elena E Balashova
- Institute of Biomedical Chemistry, Pogodinskaya St. 10, Moscow 119121, Russia.
| | - Dmitry L Maslov
- Institute of Biomedical Chemistry, Pogodinskaya St. 10, Moscow 119121, Russia.
| | - Petr G Lokhov
- Institute of Biomedical Chemistry, Pogodinskaya St. 10, Moscow 119121, Russia.
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32
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Aringhieri S, Carli M, Kolachalam S, Verdesca V, Cini E, Rossi M, McCormick PJ, Corsini GU, Maggio R, Scarselli M. Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences. Pharmacol Ther 2018; 192:20-41. [PMID: 29953902 DOI: 10.1016/j.pharmthera.2018.06.012] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in symptoms severity, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors. This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of "atypia" that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum. Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of "atypia". Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.
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Affiliation(s)
- Stefano Aringhieri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Marco Carli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Shivakumar Kolachalam
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Valeria Verdesca
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Enrico Cini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Mario Rossi
- Institute of Molecular Cell and Systems Biology, University of Glasgow, UK
| | - Peter J McCormick
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK
| | - Giovanni U Corsini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Roberto Maggio
- Biotechnological and Applied Clinical Sciences Department, University of L'Aquila, Italy
| | - Marco Scarselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy.
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33
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Mauri MC, Paletta S, Di Pace C, Reggiori A, Cirnigliaro G, Valli I, Altamura AC. Clinical Pharmacokinetics of Atypical Antipsychotics: An Update. Clin Pharmacokinet 2018; 57:1493-1528. [DOI: 10.1007/s40262-018-0664-3] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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34
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Pereira SAP, Costa SPF, Cunha E, Passos MLC, Araújo ARST, Saraiva MLMFS. Manual or automated measuring of antipsychotics' chemical oxygen demand. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2018; 152:55-60. [PMID: 29407782 DOI: 10.1016/j.ecoenv.2018.01.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 01/03/2018] [Accepted: 01/10/2018] [Indexed: 06/07/2023]
Abstract
Antipsychotic (AP) drugs are becoming accumulated in terrestrial and aqueous resources due to their actual consumption. Thus, the search of methods for assessing the contamination load of these drugs is mandatory. The COD is a key parameter used for monitoring water quality upon the assessment of the effect of polluting agents on the oxygen level. Thus, the present work aims to assess the chemical oxygen demand (COD) levels of several typical and atypical antipsychotic drugs in order to obtain structure-activity relationships. It was implemented the titrimetric method with potassium dichromate as oxidant and a digestion step of 2h, followed by the measurement of remained unreduced dichromate by titration. After that, an automated sequential injection analysis (SIA) method was, also, used aiming to overcome some drawbacks of the titrimetric method. The results obtained showed a relationship between the chemical structures of antipsychotic drugs and their COD values, where the presence of aromatic rings and oxidable groups give higher COD values. It was obtained a good compliance between the results of the reference batch procedure and the SIA system, and the APs were clustered in two groups, with the values ratio between the methodologies, of 2 or 4, in the case of lower or higher COD values, respectively. The SIA methodology is capable of operating as a screening method, in any stage of a synthetic process, being also more environmentally friendly, and cost-effective. Besides, the studies presented open promising perspectives for the improvement of the effectiveness of pharmaceutical removal from the waste effluents, by assessing COD values.
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Affiliation(s)
- Sarah A P Pereira
- LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, Porto University, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Susana P F Costa
- LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, Porto University, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Edite Cunha
- LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, Porto University, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Marieta L C Passos
- LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, Porto University, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
| | - André R S T Araújo
- LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, Porto University, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Unidade de Investigação para o Desenvolvimento do Interior, Instituto Politécnico da Guarda, Av. Dr. Francisco de Sá Carneiro, n° 50, 6300-559 Guarda, Portugal.
| | - M Lúcia M F S Saraiva
- LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, Porto University, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
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35
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Miroshnichenko II, Baymeeva NV. Simultaneous Determination of Antipsychotic Drugs and Their Active Metabolites by LC–MS-MS and its Application to Therapeutic Drug Monitoring. J Chromatogr Sci 2018; 56:510-517. [DOI: 10.1093/chromsci/bmy024] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Indexed: 02/02/2023]
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36
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Pouliopoulos A, Tsakelidou E, Krokos A, Gika HG, Theodoridis G, Raikos N. Quantification of 15 Psychotropic Drugs in Serum and Postmortem Blood Samples after a Modified Mini-QuEChERS by UHPLC–MS-MS. J Anal Toxicol 2018; 42:337-345. [DOI: 10.1093/jat/bky006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Indexed: 11/14/2022] Open
Affiliation(s)
- A Pouliopoulos
- Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki 541 24 Thessaloniki, Greece
| | - E Tsakelidou
- Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki 541 24 Thessaloniki, Greece
| | - A Krokos
- Department of Chemistry, Laboratory of Analytical Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
| | - H G Gika
- Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki 541 24 Thessaloniki, Greece
| | - G Theodoridis
- Department of Chemistry, Laboratory of Analytical Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
| | - N Raikos
- Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki 541 24 Thessaloniki, Greece
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37
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Santini SA, Panza F, Lozupone M, Bellomo A, Greco A, Seripa D. Genetics of tailored medicine: Focus on CNS drugs. Microchem J 2018. [DOI: 10.1016/j.microc.2017.02.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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38
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Pereira SAP, Costa SPF, Cunha E, Passos MLC, Araújo ARST, Saraiva MLMFS. Biodegradability of several antipsychotic drugs: manual and automatic assessment. NEW J CHEM 2018. [DOI: 10.1039/c8nj01636d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
For the first time, the biodegradability values were determined for several antipsychotic drugs.
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Affiliation(s)
- Sarah A. P. Pereira
- LAQV, REQUIMTE
- Department of Chemical Sciences
- Laboratory of Applied Chemistry
- Faculty of Pharmacy
- Porto University
| | - Susana P. F. Costa
- LAQV, REQUIMTE
- Department of Chemical Sciences
- Laboratory of Applied Chemistry
- Faculty of Pharmacy
- Porto University
| | - Edite Cunha
- LAQV, REQUIMTE
- Department of Chemical Sciences
- Laboratory of Applied Chemistry
- Faculty of Pharmacy
- Porto University
| | - Marieta L. C. Passos
- LAQV, REQUIMTE
- Department of Chemical Sciences
- Laboratory of Applied Chemistry
- Faculty of Pharmacy
- Porto University
| | - André R. S. T. Araújo
- LAQV, REQUIMTE
- Department of Chemical Sciences
- Laboratory of Applied Chemistry
- Faculty of Pharmacy
- Porto University
| | - M. Lúcia M. F. S. Saraiva
- LAQV, REQUIMTE
- Department of Chemical Sciences
- Laboratory of Applied Chemistry
- Faculty of Pharmacy
- Porto University
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39
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Modak AS. Point-of-care companion diagnostic tests for personalizing psychiatric medications: fulfilling an unmet clinical need. J Breath Res 2017; 12:017101. [PMID: 28920579 DOI: 10.1088/1752-7163/aa8d2e] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Over the last decade stable isotope-labeled substrates have been used as probes for rapid, point-of-care, non-invasive and user-friendly phenotype breath tests to evaluate activity of drug metabolizing enzymes. These diagnostic breath tests can potentially be used as companion diagnostics by physicians to personalize medications, especially psychiatric drugs with narrow therapeutic windows, to monitor the progress of disease severity, medication efficacy and to study in vivo the pharmacokinetics of xenobiotics. Several genotype tests have been approved by the FDA over the last 15 years for both cytochrome P450 2D6 and 2C19 enzymes, however they have not been cleared for use in personalizing medications since they fall woefully short in identifying all non-responders to drugs, especially for the CYP450 enzymes. CYP2D6 and CYP2C19 are among the most extensively studied drug metabolizing enzymes, involved in the metabolism of approximately 30% of FDA-approved drugs in clinical use, associated with large individual differences in medication efficacy or tolerability essentially due to phenoconversion. The development and commercialization via FDA approval of the non-invasive, rapid (<60 min), in vivo, phenotype diagnostic breath tests to evaluate polymorphic CYP2D6 and CYP2C19 enzyme activity by measuring exhaled 13CO2 as a biomarker in breath will effectively resolve the currently unmet clinical need for individualized psychiatric drug therapy. Clinicians could personalize treatment options for patients based on the CYP2D6 and CYP2C19 phenotype by selecting the optimal medication at the right initial and subsequent maintenance dose for the desired clinical outcome (i.e. greatest efficacy and minimal side effects).
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Affiliation(s)
- Anil S Modak
- Cambridge Isotope Laboratories, Inc., 3 Highwood Drive, Tewksbury, MA 01876, United States of America
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40
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Abstract
The newer atypical antipsychotic agents (AAPs) represent an attractive therapeutic option for a wide range of psychotic disorders, including schizophrenia and bipolar mania, because of the reduced risk of disabling extrapyramidal symptoms. However, their growing use has raised questions about their tolerability over the endocrine, metabolic, and cardiovascular axes. Indeed, atypical antipsychotic drugs are associated, to differing extents, with mild elevation of aminotransferases related to weight gain, AAP-induced metabolic syndrome, and nonalcoholic fatty liver disease. Although the hepatic safety of new AAPs seems improved over that of chlorpromazine, they can occasionally cause idiosyncratic liver injury with varying phenotypes and, rarely, lead to acute liver failure. However, AAPs are a group of heterogeneous, chemically unrelated compounds with distinct pharmacological and pharmacokinetic properties and substantially different safety profiles, which precludes the notion of a class effect for hepatotoxicity risk and highlights the need for an individualized therapeutic approach. We discuss the current evidence on the hepatotoxicity potential of AAPs, the emerging underlying mechanisms, and the limitations inherent to this group of drugs for both establishing a proper causality assessment and developing strategies for risk management.
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Corsi-Zuelli FMDG, Brognara F, Quirino GFDS, Hiroki CH, Fais RS, Del-Ben CM, Ulloa L, Salgado HC, Kanashiro A, Loureiro CM. Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Activation of the Alpha-7 Nicotinic Acetylcholine Receptor. Front Immunol 2017; 8:618. [PMID: 28620379 PMCID: PMC5449450 DOI: 10.3389/fimmu.2017.00618] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 05/10/2017] [Indexed: 12/28/2022] Open
Abstract
Schizophrenia is one of the most debilitating mental disorders and is aggravated by the lack of efficacious treatment. Although its etiology is unclear, epidemiological studies indicate that infection and inflammation during development induces behavioral, morphological, neurochemical, and cognitive impairments, increasing the risk of developing schizophrenia. The inflammatory hypothesis of schizophrenia is also supported by clinical studies demonstrating systemic inflammation and microglia activation in schizophrenic patients. Although elucidating the mechanism that induces this inflammatory profile remains a challenge, mounting evidence suggests that neuroimmune interactions may provide therapeutic advantages to control inflammation and hence schizophrenia. Recent studies have indicated that vagus nerve stimulation controls both peripheral and central inflammation via alpha-7 nicotinic acetylcholine receptor (α7nAChR). Other findings have indicated that vagal stimulation and α7nAChR-agonists can provide therapeutic advantages for neuropsychiatric disorders, such as depression and epilepsy. This review analyzes the latest results regarding: (I) the immune-to-brain pathogenesis of schizophrenia; (II) the regulation of inflammation by the autonomic nervous system in psychiatric disorders; and (III) the role of the vagus nerve and α7nAChR in schizophrenia.
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Affiliation(s)
| | - Fernanda Brognara
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | | | - Carlos Hiroji Hiroki
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Rafael Sobrano Fais
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Cristina Marta Del-Ben
- Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Luis Ulloa
- Department of Surgery, Center of Immunology and Inflammation, Rutgers University-New Jersey Medical School, Newark, NJ, United States
| | - Helio Cesar Salgado
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Alexandre Kanashiro
- Department of Physiological Sciences, Federal University of São Carlos, São Carlos, Brazil
| | - Camila Marcelino Loureiro
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
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Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: Role of 5-HT 2A receptor agonism. Eur Neuropsychopharmacol 2017; 27:383-398. [PMID: 28283227 DOI: 10.1016/j.euroneuro.2017.02.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 02/01/2017] [Accepted: 02/21/2017] [Indexed: 02/04/2023]
Abstract
Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on the concept that SGAs have reduced motor side effects. With this premise, this study examined in HeLa and other cell lines the effects of different APDs on the activation of ERK1/2 (Extracellular signal-regulated kinases) and AKT (Protein Kinase B) kinases, which may be affected in schizophrenia and bipolar disorder. Among the SGAs, Clozapine clearly resulted as the most effective drug inducing ERK1/2 phosphorylation with potency in the low micromolar range. Quetiapine and Olanzapine showed a maximal response of about 50% compared to Clozapine, while FGAs such as Haloperidol and Sulpiride did not have any relevant effect. Among FGAs, Chlorpromazine was able to partially activate ERK1/2 at 30% compared to Clozapine. Referring to AKT activation, Clozapine, Quetiapine and Olanzapine demonstrated a similar efficacy, while FGAs, besides Chlorpromazine, were incapable to obtain any particular biological response. In relation to ERK1/2 activation, we found that 5-HT2A serotonin receptor antagonists Ketanserin and M100907, both partially reduced Clozapine effect. In addition, we also observed an increase of potency of Clozapine effect in HeLa transfected cells with recombinant 5-HT2A receptor and in rat glioma C6 cells that express a higher amount of this receptor. This indicates that ERK1/2 stimulation induced by Clozapine could, to some extent, be mediated by 5-HT2A receptor, through a novel mechanism that is called "biased agonism", even though other cellular targets are involved. This evidence may be relevant to explain the superiority of Clozapine among the APDs.
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43
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Pairas GN, Perperopoulou F, Tsoungas PG, Varvounis G. The Isoxazole Ring and ItsN-Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics. ChemMedChem 2017; 12:408-419. [DOI: 10.1002/cmdc.201700023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 02/13/2017] [Indexed: 01/23/2023]
Affiliation(s)
- George N. Pairas
- Laboratory of Medicinal Chemistry, Department of Pharmacy; University of Patras; 265 04 Patras Greece
| | - Fereniki Perperopoulou
- Laboratory of Enzyme Technology, Department of Biotechnology; Agricultural University of Athens; 75 Iera Odos St. 118 55 Athens Greece
| | - Petros G. Tsoungas
- Laboratory of Biochemistry; Hellenic Pasteur Institute; 127 Vas. Sofias Ave. 115 21 Athens Greece
| | - George Varvounis
- Section of Organic Chemistry and Biochemistry, Department of Chemistry; University of Ioannina; 451 10 Ioannina Greece
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Kiss A, Majercikova Z. Repeated asenapine treatment does not participate in the mild stress induced FosB/ΔFosB expression in the rat hypothalamic paraventricular nucleus neurons. Neuropeptides 2017; 61:57-65. [PMID: 27756486 DOI: 10.1016/j.npep.2016.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 10/13/2016] [Accepted: 10/13/2016] [Indexed: 01/15/2023]
Abstract
Effect of repeated asenapine (ASE) treatment on FosB/ΔFosB expression was studied in the hypothalamic paraventricular nucleus (PVN) of male rats exposed to chronic mild stress (CMS) for 21days. Our intention was to find out whether repeated ASE treatment for 14days may: 1) induce FosB/ΔFosB expression in the PVN; 2) activate selected PVN neuronal phenotypes, synthesizing oxytocin (OXY), vasopressin (AVP), corticoliberin (CRH) or tyrosine hydroxylase (TH); and 3) interfere with the impact of CMS. Control, ASE, CMS, and CMS+ASE treated groups were used. CMS included restraint, social isolation, crowding, swimming, and cold. From the 7th day of CMS, rats received ASE (0.3mg/kg) or saline (300μl/rat) subcutaneously, twice a day for 14days. They were sacrificed on the day 22nd (16-18h after last treatments). FosB/ΔFosB was visualized with avidin biotin peroxidase complex and OXY, AVP, CRH or TH antibodies by fluorescent dyes. Saline and ASE did not promote FosB/ΔFosB expression in the PVN. CMS and CMS+ASE elicited FosB/ΔFosB-expression in the PVN, whereas, ASE did not augment or attenuate FosB/ΔFosB induction elicited by CMS. FosB/ΔFosB-CRH occurred after CMS and CMS+ASE treatments in the PVN middle sector, while FosB/ΔFosB-AVP and FosB/ΔFosB-OXY after CMS and CMS+ASE treatments in the PVN posterior sector. FosB/ΔFosB-TH colocalization was rare. Larger FosB/ΔFosB profiles, running above the PVN, did not show any colocalizations. The study provides an anatomical/functional knowledge about an unaccented nature of prolonged ASE treatment at the level of PVN and excludes its positive or negative interplay with CMS effect. Data indicate that long-lasting ASE treatment might not act as a stressor acting at the PVN level.
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Affiliation(s)
- Alexander Kiss
- Institute of Experimental Endocrinology, Biomedial Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
| | - Zuzana Majercikova
- Institute of Experimental Endocrinology, Biomedial Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
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Shafrin J, May SG, Shrestha A, Ruetsch C, Gerlanc N, Forma F, Hatch A, Lakdawalla DN, Lindenmayer JP. Access to credible information on schizophrenia patients' medication adherence by prescribers can change their treatment strategies: evidence from an online survey of providers. Patient Prefer Adherence 2017; 11:1071-1081. [PMID: 28721020 PMCID: PMC5499864 DOI: 10.2147/ppa.s135957] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [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
OBJECTIVE Overestimating patients' medication adherence diminishes the ability of psychiatric care providers to prescribe the most effective treatment and to identify the root causes of treatment resistance in schizophrenia. This study was conducted to determine how credible patient drug adherence information (PDAI) might change prescribers' treatment decisions. METHODS In an online survey containing 8 clinical case vignettes describing patients with schizophrenia, health care practitioners who prescribe antipsychotics to patients with schizophrenia were instructed to choose a preferred treatment recommendation from a set of predefined pharmacologic and non-pharmacologic options. The prescribers were randomly assigned to an experimental or a control group, with only the experimental group receiving PDAI. The primary outcome was the prescribers' treatment choice for each case. Between-group differences were analyzed using multinomial logistic regression. RESULTS A convenience sample (n=219) of prescribers completed the survey. For 3 nonadherent patient vignettes, respondents in the experimental group were more likely to choose a long-acting injectable antipsychotic compared with those in the control group (77.7% experimental vs 25.8% control; P<0.001). For 2 adherent but poorly controlled patient vignettes, prescribers who received PDAI were more likely to increase the antipsychotic dose compared with the control group (49.1% vs 39.1%; P<0.001). For the adherent and well-controlled patient vignette, respondents in both groups made similar treatment recommendations across all choices (P=0.099), but respondents in the experimental arm were more likely to recommend monitoring clinical stability (87.2% experimental vs 75.5% control, reference group). CONCLUSION The results illustrate how credible PDAI can facilitate more appropriate clinical decisions for patients with schizophrenia.
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Affiliation(s)
- Jason Shafrin
- Precision Health Economics, Los Angeles, CA
- Correspondence: Jason Shafrin, Precision Health Economics, 11100 Santa Monica Blvd, Suite 500, Los Angeles, CA 90025, USA, Tel +1 310 984 7705, Fax +1 310 982 6311, Email
| | | | | | | | | | - Felicia Forma
- Otsuka Pharmaceutical Development & Commercialization, Inc
| | | | - Darius N Lakdawalla
- Precision Health Economics, Los Angeles, CA
- Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, CA
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Preparation of magnetic ODS-PAN thin-films for microextraction of quetiapine and clozapine in plasma and urine samples followed by HPLC-UV detection. J Pharm Biomed Anal 2016; 125:319-28. [DOI: 10.1016/j.jpba.2016.04.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 04/05/2016] [Accepted: 04/05/2016] [Indexed: 11/21/2022]
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Development and validation of HILIC-ESI/MS/MS methods for simultaneous quantitation of several antipsychotics in human plasma and blood. Bioanalysis 2016; 8:765-94. [PMID: 27005848 DOI: 10.4155/bio.16.27] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Knowledge of antipsychotic drug levels at point of care (POC) may significantly aid therapeutic decision-making. To support the development of future POC devices and to validate the use of fingerstick capillary blood sampling, two robust hydrophilic interaction LC-ESI/MS/MS methods were developed and validated. Two PK studies were completed evaluating the correlation between fingerstick blood and plasma concentrations with corresponding venous blood and plasma concentrations for several commonly prescribed atypical antipsychotics and selected metabolites. Sensitive and reliable LC-MS/MS bioanalytical assays were developed to support these studies. RESULTS Three methods, requiring only 25-μl matrix volumes, were developed using supported liquid extraction with hydrophilic interaction LC-MS/MS detection and validated according to regulatory guidance. CONCLUSION Robust and efficient LC-MS/MS assays were established and were effective in providing antipsychotic drug matrix comparator results in the intended clinical studies.
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Kacirova I, Grundmann M, Silhan P, Brozmanova H. A Case Report of Clonazepam Dependence: Utilization of Therapeutic Drug Monitoring During Withdrawal Period. Medicine (Baltimore) 2016; 95:e2881. [PMID: 26945373 PMCID: PMC4782857 DOI: 10.1097/md.0000000000002881] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ∼60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence.
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Affiliation(s)
- Ivana Kacirova
- From the Department of Clinical Pharmacology (IK, MG, HB), Faculty of Medicine, University of Ostrava; Department of Clinical Pharmacology (IK, HB), Department of Laboratory Diagnostics; and Department of Psychiatry (PS), University Hospital Ostrava, Czech Republic
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Spina E, Hiemke C, de Leon J. Assessing drug-drug interactions through therapeutic drug monitoring when administering oral second-generation antipsychotics. Expert Opin Drug Metab Toxicol 2016; 12:407-22. [DOI: 10.1517/17425255.2016.1154043] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Eftekhari A, Azarmi Y, Parvizpur A, Eghbal MA. Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes. Xenobiotica 2015; 46:369-78. [PMID: 26364812 DOI: 10.3109/00498254.2015.1078522] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
1. Olanzapine (OLZ) is a widely used atypical antipsychotic agent for the treatment of schizophrenia and other disorders. Serious hepatotoxicity and elevated liver enzymes have been reported in patients receiving OLZ. However, the cellular and molecular mechanisms of the OLZ hepatotoxicity are unknown. 2. In this study, the cytotoxic effect of OLZ on freshly isolated rat hepatocytes was assessed. Our results showed that the cytotoxicity of OLZ in hepatocytes is mediated by overproduction of reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation preceding cell lysis. All the aforementioned OLZ-induced cellular events were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate generators. Also, the present results demonstrated that CYP450 is involved in OLZ-induced oxidative stress and cytotoxicity mechanism. 3. It is concluded that OLZ hepatotoxicity is associated with both mitochondrial/lysosomal involvement following the initiation of oxidative stress in hepatocytes.
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Affiliation(s)
- Aziz Eftekhari
- a Biotechnology Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .,b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .,c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and.,d Students' Research Committee, Tabriz University of Medical Sciences , Tabriz , Iran
| | - Yadollah Azarmi
- b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .,c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and
| | - Alireza Parvizpur
- b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .,c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and
| | - Mohammad Ali Eghbal
- b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .,c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and
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