Clozapine and global cognition in schizophrenia.
OBJECTIVE
Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite-N-desmethylclozapine (NDMC)-could explain these discrepancies.


METHODS
Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC.


RESULTS
Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model.


CONCLUSIONS
After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition.
Rajji
Tarek K
TK
Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Toronto, Canada.
Uchida
Hiroyuki
H
Ismail
Zahinoor
Z
Ng
Wenzie
W
Mamo
David C
DC
Remington
Gary
G
Pollock
Bruce G
BG
Mulsant
Benoit H
BH
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012189:Retrospective Studies; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index
D014150:Antipsychotic Agents; D011976:Receptors, Muscarinic; C058272:norclozapine; D003024:Clozapine