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PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia.

AbstractOBJECTIVE:
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.
METHOD:
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.
AuthorsS Kapur, R Zipursky, G Remington, C Jones, G McKay, S Houle
JournalThe American journal of psychiatry (Am J Psychiatry) Vol. 154 Issue 11 Pg. 1525-9 (Nov 1997) ISSN: 0002-953X [Print] UNITED STATES
PMID9356559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Dopamine Antagonists
  • Fluorine Radioisotopes
  • Pyrimidinones
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Salicylamides
  • Raclopride
  • setoperone
  • Loxapine
Topics
  • Adult
  • Cerebellum (drug effects, metabolism, radionuclide imaging)
  • Corpus Striatum (drug effects, metabolism, radionuclide imaging)
  • Dopamine Antagonists
  • Female
  • Fluorine Radioisotopes
  • Humans
  • Loxapine (pharmacokinetics, pharmacology, therapeutic use)
  • Male
  • Pyrimidinones
  • Raclopride
  • Receptors, Dopamine D2 (drug effects, metabolism)
  • Receptors, Serotonin (drug effects, metabolism)
  • Salicylamides
  • Schizophrenia (drug therapy, radionuclide imaging)
  • Tomography, Emission-Computed

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