Cholinergic and Anticholinergic Balances Affect Working Memory in Schizophrenia

Joel Yager, MD reviewing Rajji TK et al. Am J Psychiatry 2015 Apr 10.

The ratio of clozapine to its major metabolite, which has a divergent effect on muscarinic receptors, correlated negatively with working memory performance in schizophrenia.

Impaired working memory, a core feature of schizophrenia, is not significantly improved by clozapine or other antipsychotics and is hypothesized to occur partly via both abnormal cholinergic transmission in schizophrenia and the anticholinergic burden of medications. Clozapine antagonism at muscarinic M1, M3, and M5 receptors is thought to detrimentally affect cognition. Because clozapine and its metabolites have different and sometimes opposing effects on cholinergic transmission, investigators examined whether a high ratio of clozapine to its major metabolite N-desmethylclozapine (NDMC), a strong partial muscarinic agonist, might harm working memory.

Thirty clinically stable patients with schizophrenia who were taking clozapine at doses that had not changed for ≥4 weeks completed positive and negative symptom scales and a battery examining seven cognitive domains (working memory, processing speed, attention/vigilance, visual learning, verbal learning, reasoning and problem solving, and social cognition). Working memory performance correlated strongly and negatively with the clozapine-NDMC ratio but not with either substance's concentration, age, sex, education, or schizophrenia symptoms. Serum anticholinergic activity was measured; it correlated with clozapine concentration but not with working memory performance. Regarding the other cognitive domains, no significant effects were seen with the clozapine/NDMC ratio, either substance's concentration, or serum anticholinergic activity.

CITATION(S):

Rajji TK et al. Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine. Am J Psychiatry 2015 Apr 10; [e-pub].