1. ¹Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA
2. ²Department of Electrical Engineering and Computer Science, Vanderbilt University School of Medicine, Nashville, TN, USA
3. ³Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence: Dr RM Kessler, Department of Radiology, Vanderbilt University School of Medicine, 21st and Garland Avenue, Nashville, TN 37232, USA. Tel: +1 615 343 3938; Fax: +1 615 343 6531; E-mail: Robert.kessler@vanderbilt.edu

Received 4 November 2005; Revised 23 March 2006; Accepted 25 April 2006; Published online 31 May 2006.

Abstract

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 D₂ receptors (DA D₂r) 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 D₂r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D₂r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D₂r using PET with [¹⁸F]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 D₂r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D₂r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D₂r, 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 D₂r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D₂r. 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 D₂r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D₂r, sparing occupancy of substantia nigra receptors, and non-DA D₂r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.