A model of anticholinergic activity of atypical antipsychotic medications.
BACKGROUND
Atypical antipsychotics clozapine, olanzapine, and quetiapine have significant affinity for the muscarinic receptors in vitro, while aripiprazole, risperidone, and ziprasidone do not. Dissimilarity in binding profiles may contribute to the reported differences in the anticholinergic effects of these antipsychotics. However, it is difficult with the available data to predict the likelihood of anticholinergic effects occurring with various doses of an atypical antipsychotic.


METHODS
We developed a model to assess the potential anticholinergic activity (AA) of atypical antipsychotics at therapeutic doses. A radioreceptor assay was used to measure in vitro AA at 6 clinically relevant concentrations of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Using published pharmacokinetic data, in combination with the measured in vitro AA, dose-AA curves were generated.


RESULTS
Clozapine, and to a lesser extent olanzapine and quetiapine showed dose-dependent increases in AA. At therapeutic doses, the AA (in pmol/mL of atropine equivalents) was estimated to range from 27-250, 1-15, and 0-5.4 pmol/mL for clozapine, olanzapine, and quetiapine, respectively. Aripiprazole, risperidone, and ziprasidone did not demonstrate AA at any of the concentrations studied.


CONCLUSIONS
Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant AA.
Chew
Marci L
ML
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Mulsant
Benoit H
BH
Pollock
Bruce G
BG
Lehman
Mark E
ME
Greenspan
Andrew
A
Kirshner
Margaret A
MA
Bies
Robert R
RR
Kapur
Shitij
S
Gharabawi
Georges
G
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000068180:Aripiprazole; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology; D003987:Dibenzothiazepines / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D000069348:Quetiapine Fumarate; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D011950:Receptors, Cholinergic / Q000378:metabolism*; D018967:Risperidone / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000453:epidemiology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D015363:Quinolones; D011950:Receptors, Cholinergic; D013844:Thiazoles; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; C092292:ziprasidone; D000068180:Aripiprazole; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine