Decreased 5-HT2a Receptor Binding in Patients with Anorexia Nervosa Kurt Audenaert, MD, PhD1,2; Koen Van Laere, MD, PhD, DrSc2; Filip Dumont, PhD3; Miriam Vervaet, PhD1; Ingeborg Goethals, MD2; Guido Slegers, PhD3; John Mertens, PhD4; Cees van Heeringen, MD, PhD1; and Rudi A. Dierckx, MD, PhD2 1Department of Psychiatry and Medical Psychology, Ghent University Hospital, Ghent, Belgium; 2Division of Nuclear Medicine, Ghent University Hospital, Ghent, Belgium; 3Department of Radiopharmacy, Ghent University, Ghent, Belgium; and 4VUB-Cyclotron, Brussels, Belgium intake, sometimes accompanied by purging behavior (i.e., Indirect estimations of brain neurotransmitters in patients with self-induced vomiting or the misuse of laxatives or diuret- anorexia nervosa (AN) and low weight have demonstrated a ics). In addition, a disturbance in the perception of body reduction in brain serotonin (5-HT) turnover in general and led to shape and weight is an essential neuropsychologic feature of hypotheses about dysfunction in the 5-HT2a receptor system. It AN (1). was our aim to investigate the central 5-HT receptor binding 2a Psychologic and biologic mechanisms appear to play key index using SPECT brain imaging. Methods: The 5-HT2a recep- tors of low-weight patients with AN were studied by means of roles in the pathogenesis of AN. Neuropsychologic inves- the highly specific radioiodinated 5-HT2a receptor antagonist tigations have indicated cognitive deficits in the frontal and 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]- parietal cortices (2,3). Perceived distortion of body image 5-iodo-2-methoxybenzamide or 123I-5-I-R91150. Fifteen pa- has been associated specifically with parietal dysfunction tients with clinical diagnoses of AN and 11 age-matched healthy (4). Functional brain imaging with PET and SPECT has volunteers received intravenous injections of 185 MBq 123I-5-I- R91150 and were scanned with high-resolution brain SPECT. shown reduced parietal and frontal cortex metabolism (5) Results: Compared with healthy volunteers, patients with AN and cerebral perfusion (6). had a significantly reduced 5-HT2a binding index in the left In past decades, the involvement of serotonin as a neu- frontal cortex, the left and right parietal cortex, and the left and rotransmitter in AN was largely indicated through indirect right occipital cortex. A significant left–right asymmetry was estimations of brain serotonergic function. Impaired seroto- Ͻ noted in the frontal cortex (left right). Conclusion: These nin turnover and function were demonstrated through results are in accordance with diminished metabolic and perfu- sion of frontal and parietal cortices reported in recent neuroim- plasma measurements of tryptophan, the precursor of 5-hy- aging studies and imply localized disturbed serotonergic func- droxytryptamine (5-HT) (7) or 5-hydroxyindole acetic acid tion. The data are discussed in the light of possible confounding (5-HIAA, the metabolite of 5-HT), in cerebrospinal fluid factors related to the low-weight AN status. A regional cortical (CSF) of low-weight AN patients (8). Elevated CSF reduction in 5-HT2a binding index is not likely to be caused by a 5-HIAA concentrations have been reported in long-time general reduction in serotonergic function due to the possible weight-restored AN patients (8). Another indication of re- confounding factors. Suggestions for further research are given. duced serotonergic function in low-weight AN patients was Key Words: anorexia nervosa; serotonin; serotonin-2A recep- blunted physiologic response to the administration of selec- tor; SPECT tive pharmacologic agonists (9–11). Again, these findings J Nucl Med 2003; 44:163–169 normalized after weight restoration (10). The involvement of the 5-HT2a receptor in the pathophys- iology of AN was demonstrated indirectly via blood platelet studies, both through an enhanced mobilization of intracel- The essential features of anorexia nervosa (AN) are that lular platelet calcium content, mediated by 5-HT receptors 2 the individual refuses to maintain a minimally normal body (12), and through enhanced platelet serotonin 5-HT2a bind- weight and is intensely afraid of gaining weight. Weight ing, measured in vitro with 3H-lysergic acid diethylamide loss can be accomplished primarily through excessive phys- (13). Recently, studies with PET and 18F-altanserin as a ical exercise and through voluntary reduction in total food tracer showed reduced 5-HT2a binding in the orbitofrontal cortex in recovered bulimic patients (14). Some recent mo- lecular genetic studies in patients with eating disorders have Received Feb. 11, 2002; revision accepted Jul. 25, 2002. For correspondence or reprints contact: Dr. Kurt Audenaert, Department of demonstrated an increased frequency of one of the alleles on Psychiatry and Medical Psychology, 1K13 Ghent University Hospital, De Pintelaan 185, Ghent, Belgium. the promotor region of the 5-HT2a gene (15). Also, twin and E-mail: [email protected] family studies suggest a genetic vulnerability to AN, and the 5-HT2A RECEPTORS IN ANOREXIA NERVOSA • Audenaert et al. 163 hypothesis has been put forward that this vulnerability may Thyroid blockade was achieved by administration of a single be expressed in the central serotonergic system (16). oral dose of 100 mg potassium iodine before injection. All subjects Functional imaging techniques, such as PET and SPECT received an intravenous injection of 185 MBq 123I-5-I-R91150 in using specific 5-HT receptor ligands, make it possible to normal sitting conditions. SPECT scanning was performed using a 2 triple-head high-resolution gamma camera GCA-9300 (Toshiba evaluate in vivo receptor binding in patients with AN. Medical Systems, Oetwil am See, Switzerland) with fanbeam Preliminary research in healthy subjects has indicated that collimation. For 123I, the resulting transaxial image resolution is 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-pi- 9.5 mm in full width at half maximum. 123 peridinyl]-5-iodo-2-methoxybenzamide ( I-5-I-R91150) is Because sequential dynamic SPECT brain scans have shown a suitable ligand for imaging 5-HT2a receptors in vivo. It that the corticocerebellar ratio reaches a plateau between 90 and binds reversibly and with high affinity in vitro to 5-HT2a 110 min, reflecting pseudoequilibrium, and remains stable there- receptors (17). On average, 2% of a bolus dose of 123I-5-I- after for up to8h(18), acquisition was started between 110 and R91150 is taken up by the brain (18). Effective blockade of 140 min after tracer injection, according to previous protocols (20). A transmission scan was acquired before the emission scan, 5-HT2a receptors in vivo was demonstrated in a study of 153 patients with schizophrenia who were treated with risperi- using 3 Gd rod sources. This scan was used for subsequent done or clozapine (19). image coregistration to stereotactic coordinates. Emission images were acquired during a 40-min period. The whole-brain volume The aim of this study was to evaluate the 5-HT2a binding was acquired within the single scanning session. Images were index (BI) in patients with AN. reconstructed using filtered backprojection and corrected for scat- ter and nonuniform attenuation (21). MATERIALS AND METHODS Analysis of the scans was performed without knowledge of patient status after automatic image coregistration to stereotactic Patients space using the transmission image (BRASS; Nuclear Diagnostics Fifteen patients were included in the study. All were right Ltd., Stockholm, Sweden) (22). handed, 16–30 y old, and diagnosed as having AN according to the The method for coregistration of SPECT receptor data using criteria of the fourth edition of the Diagnostic and Statistical transmission images has been published previously (22). In short, Manual of Mental Disorders (DSM-IV) (1). Patients were re- the sequential acquisition of transmission and emission images can cruited from an inpatient eating-disorder unit in a university psy- be used to anatomically standardize the emission image using the chiatric hospital. Patients were selected by a senior psychiatrist and same linear parameters as those used for the transmission image. a senior psychologist after DSM-IV–based structured clinical in- The latter is first reoriented to a template in Talairach space, and terviews. To create a group of patients with consistent disease the same transformation is then given to the emission images. On status, only symptom-fixed patients who stayed in the hospital as the Talairach templates, a predefined volume-of-interest (VOI) set a result of resistance of the disease to treatment were included. can be constructed (originally performed on perfusion SPECT Exclusion criteria were a comorbid psychiatric, major medical, or images), which allows a user-independent sampling of the whole- neurological disorder; antidepressant, neuroleptic, or electrocon- brain volume of different patients without previously available vulsive therapy in the preceding year; substance abuse; pregnancy structural information. or lactation; and a Mini-Mental State Examination score Ͻ 28. A diagram of the VOI map (22,23) is shown in Figure 1 and a Menstrual status was noted in female patients. description of VOIs is provided in Table 1. Radioactivity estimates The patients were compared with 11 age-matched healthy vol- in the cortex were assumed to represent total ligand binding unteers (7 women, 4 men) who were recruited from hospital staff. (specific plus nonspecific binding plus free ligand) (18). Because These