TY - JOUR
T1 - The relationship between plasma clozapine concentration and clinical outcome
T2 - a cross-sectional study
AU - Yada, Yuji
AU - Kitagawa, Kohei
AU - Sakamoto, Shinji
AU - Ozawa, Atsushi
AU - Nakada, Akihiro
AU - Kashiwagi, Hiroko
AU - Okahisa, Yuko
AU - Takao, Soshi
AU - Takaki, Manabu
AU - Kishi, Yoshiki
AU - Yamada, Norihito
N1 - Funding Information:
Y.Y. has received honoraria for his participation as a speaker at educational events sponsored by Novartis and Dainippon Sumitomo. N.Y. has received unrestricted research funding from Daiichi Sankyo, Eisai, Pfizer, Otsuka, Astellas, and Merck Sharp & Dohme, which was deposited into research accounts at Okayama University. N.Y. has received honoraria for his participation as a speaker at educational events from UCB Japan, Tsumura, Pfizer, Dainippon Sumitomo, Daiichi Sankyo, Merck Sharp & Dohme, Pfizer, Eisai, Meiji‐Seika, and Mochida. M.T. has received honoraria for his participation as a speaker at educational events sponsored by Daiichi Sankyo, Takeda, Tsumura, Otsuka and Dainippon Sumitomo. S.S. has received unrestricted research funding from Eli Lilly, which was deposited into research accounts at Okayama University Hospital. S.S. has received honoraria for his participation as a speaker at an educational event sponsored by Otsuka and Meiji‐Seika. Y.K. has received honoraria for his participation as a speaker at educational events sponsored by Novartis and Dainippon Sumitomo. K.K., Y.O., A.O., A.N., H.K., and S.T. report no additional financial or other relationship relevant to this article.
Funding Information:
This work was supported by Research and Development Grants for Comprehensive Research for Persons with Disabilities from Japan Agency for Medical Research and Development (Y.Y.) (grant number 15Adk0310045h001).
Publisher Copyright:
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - AGNP reference range
KW - Schizophrenia
KW - adverse drug reaction
KW - plasma clozapine concentration
KW - therapeutic drug monitoring
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U2 - 10.1111/acps.13264
DO - 10.1111/acps.13264
M3 - Article
C2 - 33274435
AN - SCOPUS:85097761440
VL - 143
SP - 227
EP - 237
JO - Acta Psychiatrica Scandinavica
JF - Acta Psychiatrica Scandinavica
SN - 0001-690X
IS - 3
ER -
