N-desmethylclozapine: is there evidence for its antipsychotic potential?

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. We review the complex interaction between clozapine and NDMC at relevant receptor sites, notably at M1 sites where NDMC acts as an agonist and clozapine acts as an antagonist, and at D2 and D3 receptor sites, where NDMC acts as a partial agonist and clozapine as an inverse agonist. In terms of its antipsychotic potential, there is some support that higher NDMC/clozapine concentration ratios may be associated with symptom improvement; however, there are little data on NDMC alone as having specific potential antipsychotic effects. At best, NDMC shows efficacy only at very high doses in preclinical studies, particularly based on its muscarinic M1 agonism with a potential as a procognitive compound. Regarding metabolic effects, it seems that NDMC may be associated with more metabolic side effects than the parent compound clozapine, which may therefore reduce its overall tolerability profile. Although there is some suggestion based on animal data that NDMC may have a somewhat different biological profile than clozapine, clinical data on its antipsychotic efficacy are scant at this point. This makes it necessary to test NDMC alone compared with established antipsychotic compounds in clinical trials to elucidate its effects on schizophrenia symptoms, clinical outcome, and physiologic/metabolic side effects.