Clozapine is an atypical antipsychotic usually used for treatment resistant schizophrenia.
- Guide dose-adjustment towards optimal drug exposure in relation to drug efficacy and toxicity
- Impact of abnormal hepatic function
- Impact of concomitant medicines and other exogenous compounds (e.g. smoking)
- Disease resistant to drug versus inadequate drug exposure (including uncertain adherence)
- Adverse drug reaction versus underlying disease
- Note: Clozapine concentration monitoring is not a substitute for haematological monitoring, which is required regardless of efficacy
Both clozapine and norclozapine are routinely reported.
Timing of concentration sample collection
- Trough concentration – i.e. just prior to next dose being due
- Clozapine concentrations are measured after initial dose escalation over the first month of treatment but may be done early to identify poor metabolizers if toxicity is suspected.
- At steady state (consider practicalities such as testing on weekdays)
- Consider the half-life in that person
- In healthy subjects the half-life of clozapine is 12 hours (norclozapine is 13 hours) meaning with daily dosing, steady state is reached 5 days after commencing or changing dose
- In some patients (e.g. smokers) with high clearance the half-life will be shorter
- Clozapine plasma trough concentration:
- < 1000 nmol/L:
- increased drug metabolism, e.g. a drug interaction or smoking
- note that therapeutic response can be present at such concentrations
- > 2000 nmol/L:
- sample taken too soon after the dose, i.e. not a trough
- decreased drug metabolism, e.g. a drug interaction or cessation of tobacco/cannabis smoking
- < 1000 nmol/L:
- Clozapine/norclozapine ratio (to calculate, divide clozapine concentration by norclozapine concentration):
- < 0.5:
- non-adherence in the past 24 hours
- rapid metabolism.
- slow metabolism (including saturation of metabolism at high clozapine concentrations or co-prescribing of inhibitors)
- blood sample too early in dose interval
- < 0.5:
- Norclozapine is the predominant clozapine metabolite. The utility of the clozapine/norclozapine ratio is to inform interpretation of the clozapine and norclozapine concentrations. There is no association between clozapine/norclozapine ratios and clinical response. Norclozapine’s activity (e.g. efficacy as an antipsychotic) is unclear.
Factors affecting interpretation
Factors that may give a false assay result
Clozapine is highly (95%) bound in plasma to alpha-1-acid glycoprotein (AGP).
- This is a positive acute phase protein i.e. increases with inflammation. Hence, when a patient is unwell, the amount of clozapine bound to AGP increases, but free clozapine is concentration is unaffected, leading to an increase in total clozapine concentration. Total concentration is what the laboratory measures.
Dose individualisation and adjustment
- Clozapine concentrations increase proportional to dose
- Defined dose forms can lead to issues with practical prescribing. Where possible use whole tablet dosing (rounding to the nearest whole tablet)
- Dose adjustment may result in dosing outside of that which is Medsafe-approved
Contacts for help with interpretation
Medicines Information ph: 03 364 0900
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;12:603-621.
Hiemke C, Bergemann N, Clement HW, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018;51:9-62. Erratum in: Pharmacopsychiatry. 2018;51:e1.
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;32:438-47.
Northwood K, Pearson E, Arnautovska U, et al. Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis. Br J Psychiatry. 2023;222:241-245.
Siskind D, Sharma M, Pawar M, et al. Clozapine levels as a predictor for therapeutic response: A systematic review and meta-analysis. Acta Psychiatr Scand. 2021;144:422-432.
UpToDate ‘Guidelines for prescribing clozapine in schizophrenia’. Accessed 10/07/2023 (last updated 22/05/2023)
Man, W.H., Wilting, I., Heerdink, E.R. et al. Unbound Fraction of Clozapine Significantly Decreases with Elevated Plasma Concentrations of the Inflammatory Acute-Phase Protein Alpha-1-Acid Glycoprotein. Clin Pharmacokinet. 2019;58:1069–1075
Guitton C, Abbar M, Kinowski JM, et al. Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol. 1998;18:470-476