N-Desmethylclozapine: Is There Evidence for its Antipsychotic Potential?

  title={N-Desmethylclozapine: Is There Evidence for its Antipsychotic Potential?},
  author={Maria Cristina Mendoza and Jean-Pierre Lindenmayer},
  journal={Clinical Neuropharmacology},
Objective:N-Desmethylclozapine (NDMC), one of clozapine's major metabolites, has become a recent focus of study for both its antipsychotic and metabolic effects. The aim of this review is to examine NDMC's biological activity in the context of the pathophysiology of schizophrenia and to critically evaluate the few recent preclinical and clinical studies of NDMC's potential antipsychotic effects to predict its therapeutic potential. Results:We review the complex interaction between clozapine and… 

Contributions of cholinergic receptor muscarinic 1 and CYP1A2 gene variants on the effects of plasma ratio of clozapine/N-desmethylclozapine on working memory in schizophrenia

The finding that the relationship between clozapine/N-desmethylclozAPine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of cholinergic receptor muscarinic 1) supports a cholinerential mechanism underlying this relationship.

Muscarinic mechanisms in psychotic disorders.

It is proposed that an agonist with M(1) and M(4) interactions would effectively treat core symptom clusters associated with schizophrenia.

Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series

Four pediatric cases with severe psychiatric disorders underlying the experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine are reported and a detailed step-by-step multidisciplinary protocol is proposed.

Association of clozapine-related metabolic disturbances with CYP3A4 expression in patients with schizophrenia

CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy, and norclozapine/clozAPine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI.



Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

NDMC, because of its M1 agonism, may more effectively treat the cognitive impairments observed in schizophrenia than clozapine itself; and M1 receptor agonism may be a valuable target for the development of drugs that can improve cognitive deficit in schizophrenia, and perhaps other neuropsychiatric disorders as well.

Pharmacology of N-desmethylclozapine.

Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists.

The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

It is demonstrated for the first time that NDMC acts as a selective and efficacious δ-opioid receptor agonist and suggested that this unique property may contribute, at least in part, to the clinical actions of the atypical antipsychotic clozapine.

Pharmacokinetics and Pharmacodynamics of Clozapine

Careful patient selection and monitoring are required when clozapine therapy is used in patients with schizophrenia because the drug does possess significant binding affinity for different dopamine receptors, with recent evidence supporting binding to the D4 receptor subtype.

N‐desmethylclozapine: a clozapine metabolite that suppresses haemopoiesis

It is suggested that N‐desmethylclozapine, the major metabolite of clozAPine, is itself toxic or is further metabolized to an unstable compound which is toxic to haemopoietic precursors of both myeloid and erythroid lineages.

Intrinsic Efficacy of Antipsychotics at Human D2, D3, and D4 Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D2/D3 Partial Agonist

Using a cell-based functional assay, it is demonstrated that overexpression of Gαo induces constitutive activity in the human D2-like receptors (D2, D3, and D4) and it is proposed that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.

The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine’s actions?

Results are consistent with the notion that a balanced degree of activity at multiple biogenic amine receptors, including M1 muscarinic agonism, is responsible for the uniquely beneficial actions of clozapine.