INTRODUCTION: Therapeutic drug monitoring (TDM) of clozapine is a very useful method for verifying both the correct intake and the interindividual variability of its metabolism, thereby avoiding the risk of toxicity. The purposes of this paper were to discover how many patients using clozapine in common clinical practice have clozapine plasma concentration (PC) levels in the proposed reference range and to identify factors that influence clozapine PC levels. METHODS: Our study included 100 inpatients (diagnosed with schizophrenia or schizoaffective disorder) taking standard doses of clozapine (100-700 mg/day). Clozapine concentration was measured by high-performance liquid chromatography. Correlations between doses and PC levels and the influence of smoking and gender on clozapine PC levels were calculated. RESULTS: A large number of the patients (67%) had PC levels outside the proposed reference range. The clozapine PC levels were influenced by dose, gender, and cigarette smoking. CONCLUSION: The correlations between dose, gender, and cigarette smoking and clozapine PC levels highlighted by our study overlap other research. It was surprising to find such a large number of patients with clozapine PC levels outside the therapeutic range. This result suggests the importance of clozapine TDM due to misunderstood inter- and/or intraindividual variability or misestimated partial therapeutic compliance.

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Psychiatry University Hospital Brno Brno Czech Republic

Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic

Institute of Forensic Medicine St Anne's University Hospital Masaryk University Brno Czech Republic

Neuropsychiatr Dis Treat. 2019 Mar 05;15:655. doi: 10.2147/NDT.S205205. PubMed

Zobrazit více v PubMed

Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of Schizophrenia, Part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318–378. PubMed

Land R, Siskind D, McArdle P, Kisely S, Winckel K, Hollingworth S. The impact of clozapine on hospital use: a systematic review and meta-analysis. Acta Psychiatr Scand. 2017;135(4):296–309. PubMed

Bachmann CJ, Aagaard L, Bernardo M, et al. International trends in clozapine use: a study in 17 countries. Acta Psychiatr Scand. 2017;136(1):37–51. PubMed

Kim JS, Park CM, Choi J, et al. The association between season of birth, age at onset, and clozapine use in schizophrenia. Acta Psychiatr Scand. 2017;136(5):445–454. PubMed

Iqbal MM, Swati S, Aneja A, Iqbal MT, Aneja E, Haque S. Most common side effects of clozapine and their management. Int J Emerg Ment Health. 2016;18(4):1–6.

Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry. J Clin Psychiatry. 1998;59(Suppl 3):3–7. PubMed

Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1–2):9–62. PubMed

Khan A, Preskorn S. Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. J Psychiatr Pract. 2005;11(5):289–301. PubMed

Couchman L, Morgan PE, Spencer EP, Flanagan RJ. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993–2007. Ther Drug Monit. 2010;32(4):438–447. PubMed

Tang YL, Mao P, Li FM, et al. Gender, age, smoking behaviour and plasma clozapine concentrations in 193 Chinese inpatients with schizophrenia. Br J Clin Pharmacol. 2007;64(1):49–56. PubMed PMC

Gaertner I, Gaertner H, Lampe D. Therapeutic drug monitoring of clozapine and olanzapine. Similarities and differences. Psychopharmakotherap. 1999;6(3):105–109.

Rajkumar AP, Poonkuzhali B, Kuruvilla A, Jacob M, Jacob KS. Clinical predictors of serum clozapine levels in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2013;28(1):50–56. PubMed

Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry. 1999;60(1):36–40. PubMed

Jann MW, Liu HC, Wei FC, Lin SK, Hu WH, Chang WH. Gender differences in plasma clozapine levels and its metabolites in schizophrenic patients. Hum Psychopharmacol. 1997;12(5):489–495.

Ulrich S, Baumann B, Wolf R, et al. Therapeutic drug monitoring of clozapine and relapse – a retrospective study of routine clinical data. Int J Clin Pharmacol Ther. 2003;41(1):3–13. PubMed

Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24(1):70–78. PubMed

Bowskill S, Couchman L, MacCabe JH, Flanagan RJ. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged 65 years and over: data from a therapeutic drug monitoring service, 1996–2010. Hum Psychopharmacol. 2012;27(3):277–283. PubMed

Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open. 2014;4(3):e004216. PubMed PMC

Seppälä NH, Leinonen EV, Lehtonen ML, Kivistö KT. Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. Pharmacol Toxicol. 1999;85(5):244–246. PubMed

Ng W, Uchida H, Ismail Z, et al. Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study. Ther Drug Monit. 2009;31(3):360–366. PubMed

Hägg S, Spigset O, Mjörndal T, Dahlqvist R. Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2000;49(1):59–63. PubMed PMC

Raaska K, Raitasuo V, Laitila J, Neuvonen PJ. Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients. Basic Clin Pharmacol Toxicol. 2004;94(1):13–18. PubMed

Pollock BG. Gender differences in psychotropic drug metabolism. Psychopharmacol Bull. 1997;33(2):235–341. PubMed

Smith S. Gender differences in antipsychotic prescribing. Int Rev Psychiatry. 2010;22(5):472–484. PubMed

Bigos KL, Pollock BG, Stankevich BA, Bies RR. Sex differences in the pharmacokinetics and pharmacodynamics of antidepressants: an updated review. Gend Med. 2009;6(4):522–543. PubMed

Relling MV, Lin JS, Ayers GD, Evans WE. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther. 1992;52(6):643–658. PubMed

Iqbal J, Sun L, Cao J, et al. Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Proc Natl Acad Sci U S A. 2013;110(27):11115–11120. PubMed PMC

Haslemo T, Eikeseth PH, Tanum L, Molden E, Refsum H. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049–1053. PubMed

Dobrinas M, Cornuz J, Oneda B, Kohler Serra M, Puhl M, Eap CB. Impact of smoking, smoking cessation, and genetic polymorphisms on CYP1A2 activity and inducibility. Clin Pharmacol Ther. 2011;90(1):117–125. PubMed

Rüther T, Bobes J, De Hert M, et al. EPA Guidance on tobacco dependence and strategies for smoking cessation in people with mental illness. Eur Psychiatry. 2014;29(2):65–82. PubMed

Mitchell DC, Knight CA, Hockenberry J, Teplansky R, Hartman TJ. Beverage caffeine intakes in the US. Food Chem Toxicol. 2014;63:136–142. PubMed

McCutcheon R, Beck K, D’Ambrosio E, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand. 2018;137(1):39–46. PubMed PMC

Di Lorenzo R, Sagona M, Landi G, Martire L, Piemonte C, Del Giovane C. The revolving door phenomenon in an Italian Acute Psychiatric Ward: a 5-year retrospective Analysis of the potential risk factors. J Nerv Ment Dis. 2016;204(9):686–692. PubMed

Legge S, Hamshere M, Hayes RD, et al. Reasons for discontinuing clozapine: a cohort study of patients commencing treatment. Schizophr Res. 2016;174(1–3):113–119. PubMed PMC