5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation.
OBJECTIVE
Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses.


METHODS
Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained.


RESULTS
Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%.


CONCLUSIONS
Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.
Kapur
S
S
Schizophrenia Division, Clarke Institute of Psychiatry, Toronto, Ont., Canada. kapur@clarke-inst.on.ca
Zipursky
R B
RB
Remington
G
G
Jones
C
C
DaSilva
J
J
Wilson
A A
AA
Houle
S
S
D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001569:Benzodiazepines; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011388:Prolactin / Q000097:blood; D011744:Pyrimidinones; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012457:Salicylamides; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D011744:Pyrimidinones; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012457:Salicylamides; D001569:Benzodiazepines; D010890:Pirenzepine; D020891:Raclopride; D011388:Prolactin; C045359:setoperone; D000077152:Olanzapine