In Vivo Serotonin 5-HT_2A Receptor Occupancy and Quetiapine

To the Editor: Quetiapine is a novel atypical antipsychotic drug. Clinical studies report a placebo-level incidence of extrapyramidal side effects and efficacy when quetiapine is used to treat the positive and negative symptoms of schizophrenia (1). Quetiapine shows a differential in vivo affinity for D₂/5-HT_2A receptors, which are thought to be predictive of an atypical antipsychotic profile (2). In vivo, low occupancy of striatal D₂ receptors has been reported (3).

We evaluated the in vivo occupancy of 5-HT_2A receptors by quetiapine using [¹²³I]5-I-R91150—a novel, highly selective 5-HT_2A ligand—for single photon emission computed tomography (SPECT). Two patients with a DSM-IV diagnosis of schizophrenia gave written informed consent before the study began. They had been receiving quetiapine, 300 mg/day, for 7 and 11 weeks, respectively.

This image acquisition was as previously reported (4). A brain-dedicated SME 810 multidetector scanner for SPECT acquired a whole-brain multislice sequence 120 minutes after an intravenous injection of 180 MBq of [¹²³I]5-I-R91150, when corticocerebellar ratio levels were maximal and stable. Region-of-interest templates were fitted to cortical and cerebellar regions for each scanning sequence (by reference to an average brain atlas) and adjusted for brain size. The ratio of activity in cortical areas relative to those in the cerebellum (an area almost devoid of 5-HT_2A receptors) provided a measure of regional specific binding to 5-HT_2A receptors over time. The degree of competitive occupancy of 5-HT_2A receptors by antipsychotic treatment is reflected in the level of decline in the specific binding ratio in drug-treated individuals relative to those in the drug-free state (4). The frontal cortex/cerebellum ratio for Mr. A was 0.94 and for Mr. B, 1.07. These are clearly lower than the ratio of 1.40 (SD=0.05) that was reported in five drug-free healthy subjects (5) but are somewhat higher than the 0.88 (SD=0.09) and 0.87 (SD=0.09) reported in patients treated with risperidone and clozapine, respectively (4). These novel data suggest significant in vivo cortical 5-HT_2A blockade by quetiapine (at doses of 300 mg/day) and are consistent with the high ratio of 5-HT_2A/D₂ receptor occupancy observed for other atypical antipsychotic drugs.