Neuropsychopharmacology (2008) 33, 2435–2441 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Cortical and Subcortical 5-HT2A Receptor Binding in Neuroleptic-Naive First-Episode Schizophrenic Patients ,1 2 3 1 1 1 David Erritzoe* , Hans Rasmussen , Klaus T Kristiansen , Vibe G Frokjaer , Steven Haugbol , Lars Pinborg , William Baare´ 4, Claus Svarer1, Jacob Madsen5, Henrik Lublin2, Gitte M Knudsen1 and Birte Y Glenthoj2 1 2 Neurobiology Research Unit, Center for Integrated Molecular Brain Imaging, University Hospital Rigshospitalet, Copenhagen, Denmark; Center for Neuropsychiatric Schizophrenia Research, University of Copenhagen, Psychiatric University Centre Glostrup, Copenhagen, Denmark; 3Center for Neuropsychiatric Schizophrenia Research, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark; 4Danish Center for 5 Magnetic Resonance Imaging, Center for Integrated Molecular Brain Imaging, Hvidovre University Hospital, Copenhagen, Denmark; PET and Cyclotron Unit, University Hospital Rigshospitalet, Copenhagen, Denmark The serotonin 5-HT2A receptor is suspected to be involved in a number of psychiatric disorders, including schizophrenia. In particular, atypical antipsychotics have antagonistic effects on the 5-HT2A receptors, supporting a specific role of the 5-HT2A receptor in the pathophysiology of this disease. The aim of this study is to investigate cortical and subcortical 5-HT binding in neuroleptic-naive 2A schizophrenic patients. Fifteen neuroleptic-naive patients diagnosed with schizophrenia (age 27.5±4.5 years), 11 men and 4 women, and ± 15 healthy control subjects matched for age (28.5 5.7 years) and gender underwent a 40 min positron emission tomography (PET) 18 study using the 5-HT2A antagonist, [ F]altanserin, as a radioligand. PET images were co-registered to 3 T magnetic resonance images (MRIs) for each individual subject, and ROIs were applied automatically onto the individual MRIs and PET images. The cerebellum was used as a reference region. The binding potential of specific tracer binding (BPp) was used as the outcome measure. No significant difference was seen in cortical receptor distribution between patients and controls. An increase in 5-HT receptor binding in the 2A caudate nucleus was detected in the group of schizophrenic patients (0.7±0.1) when compared to the healthy controls (0.5±0.3) (p ¼ 0.02). Our results confirm other in vivo findings of no difference in cortical 5-HT2A receptor binding between first-episode antipsychotic-naive schizophrenic patients and age- and gender-matched healthy control subjects. However, a preliminary finding of increased 5-HT2A binding in the caudate nucleus requires further investigation to explore the relation of subcortical and cortical 5-HT2A receptor binding. Neuropsychopharmacology (2008) 33, 2435–2441; doi:10.1038/sj.npp.1301656; published online 20 February 2008 Keywords: PET; positron emission tomography; serotonin; 5-HT2A receptor; schizophrenia; molecular imaging INTRODUCTION Bymaster, 1999) is often higher for 5-HT2A than D2 receptors. Finally, post-mortem studies suggest a seroto- A role for serotonin in the pathophysiology of schizo- nergic dysfunction in cortical areas in schizophrenia. Eleven phrenia is supported by different observations. Gaddum (Arora and Meltzer, 1991; Bennett, 1979; Burnet et al, 1996; (1954) described that the hallucinogenic drug lysergic acid Dean and Hayes, 1996; Dean et al, 1998, 1999; Gurevich and diethylamide had structural similarity to serotonin and Joyce, 1997; Laruelle et al, 1993; Matsumoto et al, 2005; Mita could cause or exacerbate psychotic symptoms. These early et al, 1986; Pralong et al, 2000) out of 15 (Dean et al, 1996; findings led to the hypothesis that serotonin was implicated Joyce et al, 1993; Reynolds et al, 1983; Whitaker et al, 1981) in the pathophysiology of schizophrenia. Further support post-mortem studies of brains of schizophrenic patients for this comes from the notion that most atypical have reported decreased 5-HT density in cortical areas, antipsychotic drugs (AAPDs) antagonize the serotonin 2A 2A/C especially in the frontal cortex. Only two studies have (5-HT ) receptor. The affinity of AAPDs as determined 2A addressed the subcortical 5-HT density in post-mortem in vitro (Meltzer et al, 1989) and in vivo (Zhang and 2A material: Joyce et al (1993) found an increased 5-HT2A density in the ventral putamen and nucleus accumbens, *Correspondence: Dr D Erritzoe, Neurobiology Research Unit 9201, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, whereas Matsumoto et al (2005) reported no significant Copenhagen 2100, Denmark, Tel: 0045 2618 1392, Fax: 0045 3545 difference in striatum between controls and patients 6713, E-mail: [email protected] suffering from schizophrenia. Received 6 August 2007; revised 31 October 2007; accepted 7 Investigations with in vivo imaging techniques have not November 2007 supported post-mortem findings of a cortical decrease in 5-HT2A receptor binding in schizophrenic patients D Erritzoe et al 2436 5-HT2A receptor binding in schizophrenia. Three positron Scale (PANSS). All interviews were recorded on video for emission tomography (PET) studies showed no difference validation purposes. in 5-HT2A/C receptor density between schizophrenic Fifteen healthy control subjects matched for age, gender, patients and controls (Lewis et al, 1999; Okubo et al, and ethnicity were recruited from the community by 2000; Trichard et al, 1998). Only one study revealed a advertisement. None of the healthy control subjects had decreased 5-HT2A binding potential in the frontal cortex of either a history of present or prior psychiatric disorder or six neuroleptic-naive schizophrenic subjects when com- had ever used any psychotropic medication as determined pared to healthy controls (Ngan et al, 2000). The latter by SCAN interviews. publication was based on a voxel-based image analysis, Four patients had prior (n ¼ 3) or present (n ¼ 1) whereas the three prior ones were based on a region-based use of antidepressant medication (in all cases selective analysis. All four previous studies were performed on a serotonin reuptake inhibitors). Current use of benzodiaze- limited number of patients and only some of them were pines was allowed, albeit not on the day of the PET antipsychotic-naive. Three of the studies used [18F]setoper- scans. Except for one, none of the patients used any drugs of 11 one as a 5-HT2A tracer, whereas one study used [ C] abuse or fulfilled ICD-10 or DSM IV criteria for either N-methylspiperone. Owing to a relatively poor selectivity of drug abuse or drug dependence by the time of inclusion. both radiotracers for the 5-HT2A receptor, these studies are None of the healthy controls or any of the patients had a limited to the detection of receptor binding only in cortical history of significant head injury or non-psychiatric areas. In conjunction with the poor selectivity of the tracers, disorder. Both healthy controls and patients had a normal a lower ratio of 5-HT2A receptors to D2 receptors in neurological interview and examination. subcortical areas compared to cortical areas makes these ligands inadequate to measure subcortical binding. Today, Magnetic Resonance Imaging two other specific 5-HT2A radioligands are available: 11 18 18 [ C]MDL 100,907 and [ F]altanserin. [ F]altanserin has High-resolution 3D T1-weighted, sagittal, spoiled gradient a 200- to 500-fold 5-HT2A/D2 selectivity measured as 1/(5- echo scans (MPRAGE) of the head (TI/TE/TR ¼ 800/3.93/ HT2A Ki/D2 Ki) ¼ 1/(0.13–0.3/62 nM) ¼ 1/(0.002–0.005) 1540 ms, flip angle 91; matrix: 256 Â 256; 192 slices) using an (Kristiansen et al, 2005; Tan et al, 1999), making it between eight-channel head array coil were acquired in all subjects 8 and 50 times more selective for the 5-HT2A receptors than 18 on a 3 T TRIO scanner (Siemens, Erlangen, Germany) at the [ F]setoperone ((1/(1/10–25 nM) ¼ 1/(0.1–0.04) ¼ 10–25- MR department of the Copenhagen University Hospital, fold 5-HT2A/D2 selectivity (Lewis et al, 1999)). In addition, 18 Hvidovre, Denmark. the affinity of [ F]altanserin for the 5-HT2A receptor is at least 20-fold higher than for other 5-HT subtypes (Tan et al, 1999). We have previously demonstrated that [18F]altanser- [18F]altanserin PET Studies in PET with a bolus infusion design is a highly reproducible Radiosynthesis and administration. The radiosynthesis of method for reliable quantification of 5-HT receptor 2A [18F]altanserin was according to the method described binding (Haugbl et al, 2007). previously by Lemaire et al (1991). Quality control was The aim of the present PET study was to investigate performed using thin-layer chromatography and high- cortical and subcortical 5-HT receptor binding in a 2A performance liquid chromatography (HPLC). The absence group of first-episode antipsychotic-naive schizophrenic of residual solvents (methanol, THF, and DMSO) in the final patients and matched healthy controls using [18F]altanserin formulation was confirmed by 1H NMR. For each PET PET. study, 0.3–3.5 GBq of [18F]altanserin was produced with a radiochemical yield greater than 95% and a mean specific MATERIALS AND METHODS activity of 52.4±34.0 GBq/mmol. Catheters were inserted in both cubital veins for tracer infusion and blood sampling, Participants respectively. [18F]altanserin was administrated as a combi- nation of a bolus injection followed by continuous infusion Fifteen patients (11 men and 4 women) were recruited after to obtain steady state of the tracer in blood and tissue. The voluntary first-time referral to a psychiatric unit of one of bolus-infusion ratio was 1.75 h, as previously described the affiliated university hospitals in the Copenhagen area (Pinborg et al, 2003). Subjects received the maximum dose (Bisbebjerg Hospital, Rigshospitalet, Psychiatric University of 3.7 MBq/kg body weight [18F]altanserin. Centre Glostrup or Psychiatric University Centre Gentofte). The study was approved by the Ethics Committee of Copenhagen and Frederiksberg ((KF)11-061/03). The sub- Imaging.