Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine

Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D-2 receptors (DA D(2)r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D(2)r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D(2)r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D(2)r using PET with [F-18]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D(2)r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D(2)r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D(2)r, 59.8% (p = 0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p = 0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D(2)r, 46.9% (p = 0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D(2)r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D(2)r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D(2)r, sparing occupancy of substantia nigra receptors, and non-DA D(2)r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.