Yuji Yada1,2, Kohei Kitagawa2, Shinji Sakamoto1, Atsushi Ozawa3, Akihiro Nakada4, Hiroko Kashiwagi5, Yuko Okahisa1, Soshi Takao6, Manabu Takaki1, Yoshiki Kishi2, Norihito Yamada1. 1. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. 2. Okayama Psychiatric Medical Center, Okayama, Japan. 3. Kanagawa Psychiatric Center, Yokohama, Japan. 4. Shizuoka Psychiatric Medical Center, Shizuoka, Japan. 5. Department of Forensic Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry. 6. Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.
Abstract
OBJECTIVE: There is no report that statistically evaluates the therapeutic reference (350-600 ng/mL) and adverse drug reaction (ADR) range (>1000 ng/mL) of clozapine (CLZ) recommended by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) consensus guidelines in an isolated and large sampling study. METHODS: We administered CLZ to 131 Japanese patients with treatment-resistant schizophrenia in a multicenter cross-sectional study. Plasma CLZ concentrations were assayed by high-performance liquid chromatography using trough sampling. The Brief Psychiatric Rating Scale (BPRS) and severe dose-dependent ADR (sedation, myoclonus, and seizures) were analyzed statistically after adjusting for possible confounders. RESULTS: The daily CLZ dosage showed a moderately positive relationship with the plasma concentration (r = 0.49, p <0.001). Every 100 ng/mL increase in plasma CLZ concentration improved the total BPRS score 1.95% (95% CI: 0.89-3.01, p <0.001) and the odds ratio (OR) 1.38 (95% CI: 1.14-1.66, p = 0.001) for BPRS response. Compared with concentrations below 350 ng/mL CLZ, 350-600 ng/mL (11.12%; 95% CI: 2.52-19.72, p = 0.012) and 600-1000 ng/mL (11.05%; 95% CI: 2.40-19.71, p = 0.013) showed significant improvement in the total BPRS score. Dosages above 1000 ng/mL showed greater improvement (25.36%; 95% CI: 13.08-37.64, p <0.001) of the total BPRS score but more severe ADRs than dosages below 1000 ng/mL (OR: 31.72; 95% CI: 1.04-968.81, p = 0.048). CONCLUSION: The AGNP therapeutic reference range (350-600 ng/mL) is useful, and a dose above 1000 ng/mL is potentially more effective but carries the risk of severe ADRs in the central nervous system. This article is protected by copyright. All rights reserved.
OBJECTIVE: There is no report that statistically evaluates the therapeutic reference (350-600 ng/mL) and adverse drug reaction (ADR) range (>1000 ng/mL) of clozapine (CLZ) recommended by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) consensus guidelines in an isolated and large sampling study. METHODS: We administered CLZ to 131 Japanese patients with treatment-resistant schizophrenia in a multicenter cross-sectional study. Plasma CLZ concentrations were assayed by high-performance liquid chromatography using trough sampling. The Brief Psychiatric Rating Scale (BPRS) and severe dose-dependent ADR (sedation, myoclonus, and seizures) were analyzed statistically after adjusting for possible confounders. RESULTS: The daily CLZ dosage showed a moderately positive relationship with the plasma concentration (r = 0.49, p <0.001). Every 100 ng/mL increase in plasma CLZ concentration improved the total BPRS score 1.95% (95% CI: 0.89-3.01, p <0.001) and the odds ratio (OR) 1.38 (95% CI: 1.14-1.66, p = 0.001) for BPRS response. Compared with concentrations below 350 ng/mL CLZ, 350-600 ng/mL (11.12%; 95% CI: 2.52-19.72, p = 0.012) and 600-1000 ng/mL (11.05%; 95% CI: 2.40-19.71, p = 0.013) showed significant improvement in the total BPRS score. Dosages above 1000 ng/mL showed greater improvement (25.36%; 95% CI: 13.08-37.64, p <0.001) of the total BPRS score but more severe ADRs than dosages below 1000 ng/mL (OR: 31.72; 95% CI: 1.04-968.81, p = 0.048). CONCLUSION: The AGNP therapeutic reference range (350-600 ng/mL) is useful, and a dose above 1000 ng/mL is potentially more effective but carries the risk of severe ADRs in the central nervous system. This article is protected by copyright. All rights reserved.
Entities:
Keywords:
AGNP reference range; Adverse drug reaction; Plasma clozapine concentration; Schizophrenia; Therapeutic drug monitoring
Authors: Amir Krivoy; Eromona Whiskey; Henrietta Webb-Wilson; Dan Joyce; Derek K Tracy; Fiona Gaughran; James H MacCabe; Sukhwinder S Shergill Journal: Ther Adv Psychopharmacol Date: 2021-10-16
Authors: Konstantina Bampali; Filip Koniuszewski; Luca L Silva; Sabah Rehman; Florian D Vogel; Thomas Seidel; Petra Scholze; Florian Zirpel; Arthur Garon; Thierry Langer; Matthäus Willeit; Margot Ernst Journal: Br J Pharmacol Date: 2022-03-07 Impact factor: 9.473