ArticlePsychopharmacology2012
Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo.
Article in Psychopharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- Canonical and Non-Canonical Antipsychotics' Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia.International journal of molecular sciences · 2023Pooled it
- Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study.Psychopharmacology · 2018Trial
- Clozapine is a functional antagonist at cardiac human HNaunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Working memory processes and the histamine-3 receptor in schizophrenia: a [Psychopharmacology · 2025Article
- Drug-Induced Cognitive Impairment.Drug safety · 2025Review
- Rethinking Clozapine: Lights and Shadows of a Revolutionary Drug.Brain sciences · 2024Review
- Excessive Daytime Sleepiness and Insomnia Symptoms in Adolescents With Major Depressive Disorder: Prevalence, Clinical Correlates, and the Relationship With Psychiatric Medications Use.Psychiatry investigation · 2023Article
- Histaminergic regulation of food intake.Frontiers in endocrinology · 2023Review
- Peripheral biomarkers of treatment-resistant schizophrenia: Genetic, inflammation and stress perspectives.Frontiers in pharmacology · 2022Review
- Histamine HNature communications · 2021Article
- Histamine, Neuroinflammation and Neurodevelopment: A Review.Frontiers in neuroscience · 2021Review
- Potentially repurposable drugs for schizophrenia identified from its interactome.Scientific reports · 2019Article
- PharmGKB summary: clozapine pathway, pharmacokinetics.Pharmacogenetics and genomics · 2018Article
- Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine.Therapeutic advances in drug safety · 2018Review
- Clozapine as a Model for Antipsychotic Development.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2017Review
- Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital.CNS spectrums · 2014Article
- Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice.Schizophrenia bulletin · 2014Article
- Clozapine-induced cardiotoxicity in rats: Involvement of tumour necrosis factor alpha, NF-κβ and caspase-3.Toxicology reports · 2014Article
- The histaminergic network in the brain: basic organization and role in disease.Nature reviews. Neuroscience · 2013Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
rationaleThe basis of the unique clinical profile of the antipsychotic clozapine is not yet elucidated. Brain histamine receptors may play a role in schizophrenia and its treatment, but their involvement in the profile of clozapine remained unknown.
objectivesWe explored the properties of clozapine and its two metabolites, N-desmethylclozapine (NDMC) and clozapine N-oxide, at the four human histaminergic receptors. We compared their active concentrations with their blood concentrations in patients treated by clozapine. We investigated the changes in receptor densities induced in rat brain by repeated administration of a therapeutic dose of clozapine.
resultsClozapine and NDMC behaved as very potent, and partial, H(1)-receptor inverse agonists, weak, and full, H(2)-receptor inverse agonists, moderate, and protean, H(3)-receptor agonists, and moderate, and partial, H(4)-receptor agonists. Taking into account their micromolar mean blood concentrations found in 75 treated patients, and assuming that they are enriched in human brain as they are in rat brain, a full occupation of H(1)-, H(3)-, and H(4)-receptors, and a partial occupation of H(2) receptors, is expected. In agreement, repeated administration of clozapine at a therapeutic dose (20 mg/kg/day for 20 days) induced an up-regulation of H(1)- and H(2)-receptors in rat brain.
conclusionsClozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations. This interaction may substantiate, at least in part, the atypical antipsychotic profile of clozapine, as well as its central and peripheral side effects such as sedation and weight gain.
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