Evidence map›Paper›PMID 40971654›Full record

ArticleSchizophrenia bulletin2026

CYP2D6 Genotypes Do Not Affect Clozapine Levels in a Large, Multicenter Cohort: Time Has Come to Revise Food and Drug Administration's Clozapine Packet Insert.

Georgios Schoretsanitis, Nermine Laaboub, Séverine Crettol, Hasan Çağın Lenk, Line Skute Bråten, Setareh Ranjbar, Marianna Piras, Céline Dubath, Carole Grandjean, Frederik Vandenberghe and 7 more

Abstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Schizophrenia bulletin, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Georgios SchoretsanitisDepartment of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, 8008 Zurich, Switzerland.ORCID 0000-0002-3851-4117
Nermine LaaboubDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Séverine CrettolDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Hasan Çağın LenkCenter for Psychopharmacology, Diakonhjemmet Hospital, 0370 Oslo, Norway.ORCID 0000-0003-4724-7396
Line Skute BråtenCenter for Psychopharmacology, Diakonhjemmet Hospital, 0370 Oslo, Norway.
Setareh RanjbarDepartment of Psychiatry, Psychiatric Epidemiology and Psychopathology Research Center, Lausanne University Hospital and University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Marianna PirasDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Céline DubathDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Carole GrandjeanDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Frederik VandenbergheDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Nicolas AnsermotDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Franziska GammaLes Toises Psychiatry and Psychotherapy Center, 1005 Lausanne, Switzerland.
Kerstin Jessica PlessenDepartment of Psychiatry, Service of Child and Adolescent Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Armin von GuntenDepartment of Psychiatry, Service of Old Age Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Philippe ConusDepartment of Psychiatry, Service of General Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Chin Bin EapDepartment of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, University of Lausanne, Prilly, 1008 Lausanne, Switzerland.
Espen MoldenCenter for Psychopharmacology, Diakonhjemmet Hospital, 0370 Oslo, Norway.ORCID 0000-0001-6190-2751

Funding

European Union's Horizon 2020 research and innovation program 964874/REALMENTSwiss National Research Foundation 320030-120686, 324730-144064, 320030-173211, 320030-200602
6 · The paper itself

Abstract

background and hypothesisThe US Food and Drug Administration (FDA) package insert for clozapine states that cytochrome P450 (CYP) 2D6 is important in clozapine metabolism, implying that CYP2D6 genotypes should be considered in clozapine dosing. We investigated differences for clozapine concentration-to-dose (C/D) ratios, as a pharmacokinetic measure, in relation to CYP2D6 phenotype. STUDY

designLinear mixed-effect regression models were applied to investigate the association between genotype-predicted CYP2D6 metabolizer phenotypes and C/D ratios including the effects of age, sex, smoking, and sampling time in a pooled sample of three cohorts, both without and with adjusting for the interaction between cohort and CYP2D6 phenotype, as well as in separate models stratified by cohort. STUDY

resultsWe included 897 patients from three cohorts with a total of 10 428 clozapine and norclozapine measurements. We found no association between CYP2D6 phenotypes and clozapine or norclozapine C/D ratios or clozapine-to-norclozapine ratios in the pooled sample with or without adjustment for the interaction between cohort and CYP2D6 phenotype nor when analyzing three cohorts separately (P>.05 in all cases). Older patients and females had higher C/D ratios of clozapine and norclozapine (P<.001, P<.001, P<.001 and P=.02), whereas smokers had lower C/D ratios of clozapine and norclozapine as well as clozapine-to-norclozapine ratios (P<.001 for all three).

conclusionsWe reported no association between CYP2D6 genotype-predicted phenotypes and clozapine pharmacokinetics. Dose adjustment based on CYP2D6 genotyping is unlikely to be helpful in managing clozapine-treated patients. We propose that the current FDA package insert should be updated to avoid misleading prescribers.

Indexed as

Antipsychotic AgentsClozapineCytochrome P-450 CYP2D6SchizophreniaAdultCohort StudiesFemaleGenotypeHumansMaleMiddle AgedUnited StatesUnited States Food and Drug AdministrationAntipsychotic AgentsClozapineCytochrome P-450 CYP2D6norclozapineclozapineCYP2D6 genotypespoor metabolizersschizophrenia spectrum disorders (SSD)therapeutic drug monitoring

Identifiers

PMID40971654
PMCPMC13391607

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.