2026 ECNP Congress

PS03-3203

Clozapine/norclozapine ratio in therapeutic drug monitoring: clinical utility and standardisation challenges

Inés Oliveira Amat — J.J. Retuerta Rodríguez-Vilariño, R. Albillos Pérez, I. Gundín Menéndez, N. Laherran-Cantera, I. Lizarraga García · Hospital General Universitario Gregorio Marañón, Psychiatry, Madrid, Spain

2026 ECNP Congress

Introduction

Clozapine remains the gold-standard treatment for treatment-resistant schizophrenia (TRS), yet its narrow therapeutic index and interindividual pharmacokinetic variability make therapeutic drug monitoring (TDM) essential. Beyond plasma levels, the clozapine/norclozapine (C/N) ratio is a clinically useful adjunct TDM parameter reflecting metabolic activity, adherence, and drug interactions. However, whether a unified reference standard for its interpretation can be established remains unclear.

Objectives

To synthesise the available evidence on the clinical utility and interpretive value of the C/N ratio as a TDM parameter in clozapine-treated patients, and to identify key gaps in its standardisation.

Methods

A narrative review was conducted, including the AGNP Consensus Guidelines [1], a large retrospective TDM audit of over 104,000 samples from 26,796 patients [2], the APA Practice Guideline for Schizophrenia [3], the Graylands Hospital Drug Bulletin [4], and a cross-ancestry pharmacokinetic and pharmacogenomic study using a genome-wide association approach [5]. Works specifically evaluating clozapine, norclozapine, and their ratio in clinical practice were prioritised.

Results

Clozapine undergoes N-demethylation to norclozapine, primarily via CYP1A2, with additional contributions from CYP3A4 and CYP2C19. Across large TDM datasets, the median C/N ratio is approximately 1.3, and most samples fall within a range of 0.5–3.0; an empirically observed distribution rather than a formally validated reference interval. Importantly, the ratio is not stable across plasma concentrations: the median C/N ratio is approximately 1.25 at low clozapine concentrations and rises to approximately 2.08 at high concentrations, reflecting saturation of CYP1A2-mediated N-demethylation. The AGNP guidelines define an expected interval of 0.45–0.79 for the metabolite-to-parent ratio in non-smokers under trough steady-state conditions, equivalent to a C/N ratio of approximately 1.27–2.22. A C/N ratio below 0.5 may suggest non-adherence, ultra-rapid metabolism, or CYP1A2 induction (e.g. smoking), though this threshold should not be used in isolation to identify ultra-rapid metabolisers. A C/N ratio above 3.0 may indicate non-trough sampling, metabolic inhibition by co-administered drugs such as fluvoxamine, systemic inflammation, or saturation kinetics. Furthermore, a cross-ancestry pharmacokinetic and pharmacogenomic analysis demonstrated that ancestral background significantly influences the C/N ratio, highlighting the need to consider population-specific variability in its interpretation [5].

Conclusions

The C/N ratio is a clinically useful index of metabolic activity, sensitive to adherence, drug interactions and pre-analytical factors, such as sampling timing. Its interpretation alongside absolute plasma clozapine concentrations can support individualised clinical decision-making in TRS, although its implementation in routine clinical practice remains limited by the lack of routine norclozapine measurements in many centres. However, the currently available reference range lacks formal validation; the empirically observed 0.5–3.0 interval was not derived under controlled trough conditions and does not account for key confounders such as smoking status or comedication. Pending formal standardisation, serial intra-patient monitoring of the C/N ratio, comparing values within the same individual over time may represent the most clinically actionable approach, as it allows detection of meaningful metabolic shifts regardless of population-derived thresholds. This reinforces the importance of contextual interpretation of the C/N ratio rather than reliance on fixed population-based thresholds. Prospective studies are needed to establish a formally validated reference interval.

References

  1. Hiemke, C., Bergemann, N., Clement, H.W., et al., 2018. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 51 (1-02), 9–62.
  2. Couchman, L., Morgan, P.E., Spencer, E.P., Flanagan, R.J., 2010. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors. Ther. Drug Monit. 32 (4), 438–447.
  3. American Psychiatric Association, 2020. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia, third ed. APA Publishing, Washington.
  4. Graylands Hospital Drug Bulletin, 2017. Interpretation of clozapine levels. North Metropolitan Health Service – Mental Health 24 (1).
  5. Pardiñas, A.F., Kappel, D.B., Roberts, M., et al., 2023. Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample. Lancet Psychiatry 10 (3), 209–219.