Brain serotonin 5-HT1A receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635

Background: Results of postmortem studies show an elevation in serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptor density in the prefrontal and temporal cortices of patients with schizophrenia. This study examined 5-HT1A receptors in vivo in patients with schizophrenia using positron emission tomography and [carbonyl-C-11] -N-[2-[4-(2-methoxyphenyl)-1-piperazinyl-]ethyll-N-(2-pyridinyl)cyclohexane carboxamide ([C-11]WAY-100635). Methods: The 5-HT1A binding potential of 14 antipsychotic drug-naive patients with a DSM-IV diagnosis of schizophrenia was compared with that of 14 age-matched healthy controls. Positron emission tomography data were analyzed using 9 cortical regions of interest, which were delineated on a coregistered magnetic resonance image and transferred to the positron emission tomographic image, with the cerebellum as the reference region for a simplified reference tissue model. We also performed a voxel-wise comparison using statistical parametric mapping. Results: The region of interest-based analysis revealed a significant mean SD cortical 5-HT1A receptor binding potential increase of 7.1% +/- 6.4% in patients with schizophrenia (F = 2.975; P = .02); local differences were +200k in the left medial temporal cortex (F = 9.339; P = .005) and +13% in the right mediotemporal cortex (F = 4.453; P = .045). There were no significant differences in regional tracer delivery or cerebellar [C-11]WAY-100635 uptake. The voxel-based analysis also confirmed a group difference in the left medial temporal cortex. Conclusions: The biological significance of elevated 5-HT1A receptor density in schizophrenia remains unclear. Given the location of 5-HT1A receptors on pyramidal cells, this elevation may reflect an abnormal glutamatergic network. Our finding needs to be viewed in light of preclinical evidence supporting a role for 5-HT1A receptors in mediating antipsychotic action and extrapyramidal adverse effects of drugs.