title: Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine.
abstract: OBJECTIVE
  Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia.
  
  
  METHODS
  Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity.
  
  
  RESULTS
  The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains.
  
  
  CONCLUSIONS
  This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Tarek K
authors: TK
authors: Rajji
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Benoit H
authors: BH
authors: Mulsant
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Simon
authors: S
authors: Davies
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Sawsan M
authors: SM
authors: Kalache
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Christopher
authors: C
authors: Tsoutsoulas
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Bruce G
authors: BG
authors: Pollock
authors: From the Geriatric Psychiatry Division, the Campbell Family Mental Health Research Institute, and the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto, Toronto.
authors: Gary
authors: G
authors: Remington
mesh_terms: D000328:Adult; D000368:Aged; D003024:Clozapine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D011594:Psychometrics; D011618:Psychotic Disorders / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy / Q000523:psychology*; D012559:Schizophrenia / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C058272:norclozapine; D003024:Clozapine