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

Am J Psychiatry. 1997 Nov;154(11):1525-9. doi: 10.1176/ajp.154.11.1525.


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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cerebellum / diagnostic imaging*
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Corpus Striatum / diagnostic imaging*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine Antagonists
  • Female
  • Fluorine Radioisotopes
  • Humans
  • Loxapine / pharmacokinetics
  • Loxapine / pharmacology
  • Loxapine / therapeutic use*
  • Male
  • Pyrimidinones
  • Raclopride
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Salicylamides
  • Schizophrenia / diagnostic imaging
  • Schizophrenia / drug therapy*
  • Tomography, Emission-Computed*


  • Dopamine Antagonists
  • Fluorine Radioisotopes
  • Pyrimidinones
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Salicylamides
  • Raclopride
  • setoperone
  • Loxapine