Is cognitive function related to plasma ratio of Clozapine to N-Desmethylclozapine? AM J Psych.June,2015


Working memory is defective in patients with schizophrenia. Poor working memory is associated with poor functional outcome. Though muscarinic neurotransmission is postulated to play a significant role in this, improving cholinergic transmission do not seem to improve working memory. Large individual variability in cholinergic status is mentioned as an explanation. clozapine also show a range of effects on cognition ( improve, neutral, deleterious effect on cognition). Is this difference due to differential actions of clozapine and its metabolite,  N-des methyl clozapine (NDMC)?

Clozapine has antimuscarinic actions at M1,M3 and M5 while NDMC is a potent partial agonist at these sites. Plasma concentrations of NDMC can vary from 20% to 150% of clozapine concentrations. It is likely that the ratios clozapine and NDMC will have an effect on cholinergic tone and thus on cognition.

Tarek K. Rajj et al from Toronto explored the relationships between serum anticholinergic activity (SAA), clozapine concentration, NDMC concentration, and cognition. 30 adult patients with schizophrenia/ schizoaffective disorder on stable clozapine monotherapy  participated in this study.Cognition was assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB).


Working memory  was negatively correlated with clozapine/NDMC ratio. Working memory   was not correlated with age, gender, education, PANSS score, clozapine concentration, or NDMC concentration. SAA levels correlated with clozapine level but not with working memory.The association between clozapine/NDMC ratio and cognition is specific to working memory,

Limitations: This is cross sectional study. We do not know the baseline cognitive functioning of the participants. Duration of treatment with clozapine is another factor to consider,as benefits of clozapine may not be accrued if less than 6 months.

Comments: This opens several interesting clinical possibilities and precautions.  If we can inhibit the metabolism of NDMC, ( but not clozapine ) we can expect improvement in working memory. Patients with high clozapine /NDMC ratio would need special attention, they may have more working memory problems and can also experience  delirious states.

Summary of the article: 

Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine.

Rajji TK, Mulsant BH, Davies S, Kalache SM, Tsoutsoulas C, Pollock BG, Remington G.

Am J Psychiatry. 2015 Jun 1;172(6):579-85.

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