The relationship between plasma levels of clozapine and N-desmethyclozapine as well as M1 receptor polymorphism with cognitive functioning and associated cortical activity in schizophrenia

Psychiatry Res Neuroimaging. 2020 Sep 30:303:111128. doi: 10.1016/j.pscychresns.2020.111128. Epub 2020 Jun 15.

Abstract

Studies that examined the effect of clozapine on cognitive functions in schizophrenia provided contradictory results. N-desmethylclozapine (NDMC) is the major metabolite of clozapine and have procognitive effects via agonistic activity in the M1 cholinergic receptors. The rs2067477 polymorphism in the M1 receptors may play role in cognitive profile in schizophrenia. We investigated the association of plasma clozapine (PClz), NDMC (PNdmc) levels and the rs2067477 polymorphism with cognitive functions and cortical activity measured by functional near infrared spectroscopy during the N-Back task in subjects with schizophrenia (N = 50) who are under antipsychotic monotherapy with clozapine. We found that PClz and PNdmc levels were negatively, PNdmc/PClz ratio was positively correlated with immediate recall score in the Rey Auditory Verbal Learning Test. PNdmc/PClz ratio was positively correlated with cortical activity during the N-back task. M1 wild-type group (CC: wild-type) produced higher cortical activity than M1 non wild-type group (CA: heterozygote / AA: mutant) in cortical regions associated with working memory (WM). These results suggest that individual differences in clozapine's effect on short term episodic memory may be associated with PClz and PNdmc. Higher activity in the M1 wild-type group may indicate inefficient use of cortical resources and/or excessive use of certain cognitive strategies during WM performance.

Keywords: Clozapine; Cognitive functions; Functional Neuroimaging; N-desmethylclozapine; Working memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / blood
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Clozapine / analogs & derivatives*
  • Clozapine / blood*
  • Clozapine / pharmacology
  • Clozapine / therapeutic use
  • Cognition / drug effects
  • Cognition / physiology*
  • Female
  • Humans
  • Male
  • Memory, Short-Term / drug effects
  • Memory, Short-Term / physiology
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Receptor, Muscarinic M1* / genetics
  • Schizophrenia / blood*
  • Schizophrenia / drug therapy
  • Schizophrenia / genetics
  • Spectroscopy, Near-Infrared / methods

Substances

  • Antipsychotic Agents
  • Receptor, Muscarinic M1
  • norclozapine
  • Clozapine