1,119
Views
9
CrossRef citations to date
0
Altmetric
Review

Therapeutic drug monitoring of clozapine in adults with schizophrenia: a review of challenges and strategies

Pages 1211-1221 | Received 23 Apr 2021, Accepted 25 Aug 2021, Published online: 06 Sep 2021

References

  • Kennedy JL, Altar CA, Taylor DL, et al. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29(2):63–76.
  • Laursen TM, Munk-Olsen T, Vestergaard M. Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry. 2012;25(2):83–88.
  • McGrath J, Saha S, Chant D, et al. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30(1):67–76.
  • Williams AM, Park SH. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs. 2015;29(2):101–111.
  • Van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635–645.
  • Carpenter WT Jr., Davis JM. Another view of the history of antipsychotic drug discovery and development. Mol Psychiatry. 2012;17(12):1168–1173.
  • Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951.
  • Li P, Snyder GL, Vanover KE. Dopamine Targeting Drugs for the Treatment of Schizophrenia: past, Present and Future. Curr Top Med Chem. 2016;16(29):3385–3403.
  • Miyamoto S, Miyake N, Jarskog LF, et al. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry. 2012;17(12):1206–1227.
  • Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–962.
  • Miller DD. Review and management of clozapine side effects. J Clin Psychiatry. 2000;61(8):14–19.
  • Kane JM, Leucht S, Carpenter D, et al. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry. 2003;64(Suppl 12):5–19.
  • Lally J, Gaughran F, Timms P, et al. Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics. Pharmgenomics Pers Med. 2016;9:117–129.
  • Schoretsanitis G, Kuzin M, Kane JM, et al. Elevated Clozapine Concentrations in Clozapine-Treated Patients with Hypersalivation. Clin Pharmacokinet. 2021;60(3):329–335.
  • Suhas S, Kumar V, Damodharan D, et al. Comment on: “Elevated Clozapine Concentrations in Clozapine-Treated Patients with Hypersalivation.” Clin Pharmacokinet. 2021;60(8):1073–1075.
  • Varma S, Bishara D, Besag FM, et al. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol. 2011;1(2):47–66.
  • Idänpään-Heikkilä J, Alhava E, Olkinuora M, et al. Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol. 1977;11(3):193–198.
  • Claghorn J, Honigfeld G, Abuzzahab FS Sr., et al. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987;7(6):377–384.
  • Kane J. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–796.
  • Rajkumar AP, Poonkuzhali B, Kuruvilla A, et al. Clinical predictors of serum clozapine levels in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2013;28(1):50–56.
  • Yuen JWY, Kim DD, Procyshyn RM, et al. Review of the Metabolic Side-Effects of Clozapine. Front Endocrinol (Lausanne). 2021;12:609240.
  • Smith RL, Tveito M, Kyllesø L, et al. Rates of complete nonadherence among atypical antipsychotic drugs: a study using blood samples from 13,217 outpatients with psychotic disorders. Schizophr Res. 2021;228:590–596.
  • De Fazio P, Gaetano R, Caroleo M, et al. Rare and very rare adverse effects of clozapine. Neuropsychiatr Dis Treat. 2015;11:1995–2003.
  • Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162–167.
  • Atkin K, Kendall F, Gould D, et al. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry. 1996;169(4):483–488.
  • Mijovic A, MacCabe JH. Clozapine-induced agranulocytosis. Ann Hematol. 2020;99(11):2477–2482.
  • Munro J, O’Sullivan D, Andrews C, et al. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance. Br J Psychiatry. 1999;175(6):576–580.
  • Legge SE, Walters JT. Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective. Pharmacogenomics. 2019;20(4):279–290.
  • Singh A, Grover S, Malhotra P, et al. Late Onset Agranulocytosis with Clozapine Associated with HLA DR4 Responding to Treatment with Granulocyte Colony-stimulating Factor: a Case Report and Review of Literature. Clin Psychopharmacol Neurosci. 2016;14(2):212–217.
  • Lahdelma L, Appelberg B. Clozapine-induced agranulocytosis in Finland, 1982-2007: long-term monitoring of patients is still warranted. J Clin Psychiatry. 2012;73(6):837–842.
  • Dickens D, Rädisch S, Chiduza GN, et al. Cellular Uptake of the Atypical Antipsychotic Clozapine Is a Carrier-Mediated Process. Mol Pharm. 2018;15(8):3557–3572.
  • Pirmohamed M, Park K. Mechanism of clozapine-induced agranulocytosis: current status of research and implications for drug development. CNS Drugs. 1997;7(2):139–158.
  • Amanzada A, Malik IA, Nischwitz M, et al. Myeloperoxidase and elastase are only expressed by neutrophils in normal and in inflamed liver. Histochem Cell Biol. 2011;135(3):305–315.
  • Zhu W, Cadet P, Baggerman G, et al. Human white blood cells synthesize morphine: CYP2D6 modulation. J Immunol. 2005;175(11):7357–7362.
  • Tafazoli S, O’Brien PJ. Peroxidases: a role in the metabolism and side effects of drugs. Drug Discov Today. 2005;10(9):617–625.
  • Dettling M, Sachse C, Müller-Oerlinghausen B, et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry. 2000;33(6):218–220.
  • Dahl ML, Llerena A, Bondesson U, et al. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol. 1994;37(1):71–74.
  • Eiermann B, Engel G, Johansson I, et al. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol. 1997;44(5):439–446.
  • Schaber G, Wiatr G, Wachsmuth H, et al. Isolation and identification of clozapine metabolites in patient urine. Drug Metab Dispos. 2001;29(6):923–931.
  • Fang J, Coutts RT, McKenna KF, et al. Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1998;358(5):592–599.
  • Mori A, Maruo Y, Iwai M, et al. UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos. 2005;33(5):672–675.
  • Li Z, Huang M, Ichikawa J, et al. N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors. Neuropsychopharmacology. 2005;30(11):1986–1995.
  • Costa-Dookhan KA, Rajji TK, Tran VN, et al. Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistant and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia. Sci Rep. 2021;11(1):2004.
  • Tan MSA, Honarparvar F, Falconer JR, et al. A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions. Psychopharmacology (Berl). 2021;238(3):615–637.
  • Lu ML, Lane HY, Lin SK, et al. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry. 2004;65(6):766–771.
  • Schoretsanitis G, Kane JM, Ruan CJ, et al. A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients. Expert Rev Clin Pharmacol. 2019;12(7):603–621.
  • Smith RL, Kyllesø L, Haslemo T, et al. Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism. Ther Drug Monit. 2019;41(4):503–508.
  • Tugnait M, Hawes EM, McKay G, et al. N-oxygenation of clozapine by flavin-containing monooxygenase. Drug Metab Dispos. 1997;25(4):524–527.
  • Paumann-Page M, Furtmüller PG, Hofbauer S, et al. Inactivation of human myeloperoxidase by hydrogen peroxide. Arch Biochem Biophys. 2013;539(1):51–62.
  • Rensen SS, Slaats Y, Nijhuis J, et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol. 2009;175(4):1473–1482.
  • Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000;61(3):154–166.
  • Laborde E. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ. 2010;17(9):1373–1380.
  • Scott RB, Matin S, Hamilton SC. Glutathione, glutathione S-transferase, and transmembrane transport of glutathione conjugate in human neutrophil leukocytes. J Lab Clin Med. 1990;116(5):674–680.
  • Jann MW, Grimsley SR, Gray EC, et al. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet. 1993;24(2):161–176.
  • Li W, Harper PA, Tang BK, et al. Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene. Biochem Pharmacol. 1998;56(5):599–612.
  • Erichsen TJ, Ehmer U, Kalthoff S, et al. Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene. Toxicol Appl Pharmacol. 2008;230(2):252–260.
  • Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049–1053.
  • 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.
  • Cormac I, Brown A, Creasey S, et al. A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine. Acta Psychiatr Scand. 2010;121(5):393–397.
  • Faber MS. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178–184.
  • Kennedy WK, Jann MW, Kutscher EC. Clinically significant drug interactions with atypical antipsychotics. CNS Drugs. 2013;27(12):1021–1048.
  • Malik S, Lally J, Ajnakina O, et al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr Res. 2018;195:267–273.
  • Pantelis C, Adesanya A. Increased risk of neutropaenia and agranulocytosis with sodium valproate used adjunctively with clozapine. Aust N Z J Psychiatry. 2001;35(4):544–545.
  • Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother. 2003;37(6):819–821.
  • Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9(5):442–473.
  • Pardiñas AF, Nalmpanti M, Pocklington AJ, Pardiñas AF, Nalmpanti M, Pocklington AJ, Legge SE, Medway C, King A, Jansen J, Helthuis M, Zammit S, MacCabe J et al. Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism. Am J Psychiatry. 2019;176(6):477–486.
  • Sachse C, Brockmöller J, Bauer S, et al. Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999;47(4):445–449.
  • Eap CB, Bender S, Jaquenoud Sirot E, et al. Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. J Clin Psychopharmacol. 2004;24(2):214–219.
  • Smith RL, O’Connell K, Athanasiu L, et al. Correction: identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients-a genome-wide association study adjusting for smoking habits. Transl Psychiatry. 2020;10(1):366.
  • Ng CH, Chong SA, Lambert T, et al. An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels. Int Clin Psychopharmacol. 2005;20(3):163–168.
  • Schoretsanitis G, Smith RL, Molden E, et al., European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed. J Clin Psychopharmacol. 41(2): 140–147. 2021.
  • Kelly DL, Kreyenbuhl J, Dixon L, et al. Clozapine underutilization and discontinuation in African Americans due to leucopenia. Schizophr Bull. 2007;33(5):1221–1224.
  • Hiemke C, Bergemann N, Clement H, Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1–02):9–62.
  • Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry. 1991;148(2):231–235.
  • Miller DD, Fleming F, Holman TL, et al. Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry. 1994;55(Suppl):B:117–121.
  • Freudenreich O, Weiner RD, McEvoy JP. Clozapine-induced electroencephalogram changes as a function of clozapine serum levels. Biol Psychiatry. 1997;42(2):132–137.
  • Novartis Pharmaceuticals Corporation. Clozaril (clozapine). http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf. ( Accessed 19 April, 2021).
  • Bengtsson F. Therapeutic drug monitoring of psychotropic drugs. TDM “nouveau.” Ther Drug Monit. 2004;26(2):145–151.
  • Goldstein JI, Jarskog LF, Hilliard C, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nat Commun. 2014;5(1):4757.
  • Wiciński M, Węclewicz MM. Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring. Curr Opin Hematol. 2018;25(1):22–28.
  • Ma S, Subramanian R. Detecting and characterizing reactive metabolites by liquid chromatography/tandem mass spectrometry. J Mass Spectrom. 2006;41(9):1121–1139.
  • Freudenreich O, McEvoy J. https://www.uptodate.com/contents/guidelines-for-prescribing-clozapine-in-schizophrenia ( accessed April 19, 2021).
  • 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.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.