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… 

Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia

The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine and the associations between metabolic and cognitive parameters with the CLZ:NDMC ratios are investigated.

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.



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, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-d-aspartate receptor activity

  • C. SurP. Mallorga P. Conn
  • Psychology, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
Observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation.

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.

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.