PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia.
OBJECTIVE
Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses.


METHODS
Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively.


RESULTS
The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors.


CONCLUSIONS
Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.
Kapur
S
S
Schizophrenia Division, Clarke Institute of Psychiatry, University of Toronto, Canada. kapur@clarke-inst.on.ca
Zipursky
R
R
Remington
G
G
Jones
C
C
McKay
G
G
Houle
S
S
D000328:Adult; D002531:Cerebellum / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008152:Loxapine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; 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*; D014055:Tomography, Emission-Computed
D018492:Dopamine Antagonists; D005462:Fluorine Radioisotopes; D011744:Pyrimidinones; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012457:Salicylamides; D020891:Raclopride; C045359:setoperone; D008152:Loxapine