Iodine-123-Iodobenzamide SPECT Assessment of D2 Receptor Occupancy in . Treated Schizophrenic Patients

Stefan Dresel, Klaus Tatsch, Inga Dähne,Torsten Mager, Josef Scherer and Klaus Hahn Departments ofNuclear Medicine and Psychiatry, University ofMunich, Munich; and State Mental Hospital, Haar, Germany

The dopamine hypothesis has been challenged with the The recently introduced neuroleptic, risperidone, was expected to advent of atypical antipsychotics. , the archetypal block fewer dopamine D2 receptors than typical neuroleptics (e.g., drug in this group, displays remarkable clinical efficacy (7), ), but at comparable potency. The aim of this study was to evaluatethe degree of dopamineD2 receptoroccupancyin with a low propensity to induce catalepsy in rats (8). Clozapine relation to the neuroleptic dosage and to correlate the findings with has been shown to have only weak D2 receptor antagonistic the presence of extrapyramidal symptoms (EPS). Additionally, the properties in vitro, in contrast with its high affinity for a variety data were compared to previous iodobenzamide (IBZM)SPECT of other neuroreceptors (9). findings in patients treated with other neuroleptics, haloperidol and Recently, new antipsychotics have been developed, among clozapine. Methods: In 20 patients with schizophrenia [Diagnostic them rispendone, and have been licensed for clinical use. They and Statistical Manual of Mental Disorders (Third Edition-Reviseci)] are at least as effective as conventional antipsychotics but, like treated with mean daily doses of risperidone ranging from 0.029 to clozapine, have a decreased capacity to induce catalepsy in rats 0.128 mg/kg body weight, SPECT was performed 2 hr after intra (10). The pharmacological profile underlying the atypical @ venous injection of 185 MBq 1231-IBZM,a selective dopamine properties of risperidone has not yet been fully evaluated, and it receptor ligand. Striatal IBZMbinding was assessed by calculating a striatal/frontal cortex ratio, expressed as a percentage of the is unclear whether the clinical efficacy is also related to control value. Results Selective dopamine D2 receptor binding of blocking of dopamine D2 receptors. the ligand was reduced in all treated patients, with binding values The aim of this study was to evaluate the degree of D2 ranging from 7% to 68%. The degree of occupancy displayed an occupancy in relation to the neuroleptic dosage and to correlate exponential dose-response relationship (r = —0.86;p < 0.0001). the findings with the presence of extrapyramidal symptoms The slope of the curve was between those of haloperidol and (EPS). Additionally, the data were compared to our previous clozapine but was closer and more similar in shape to the curve of findings of IBZM SPECT in patients receiving treatment with haloperidol. Extrapyramidal symptoms were observed in 8 of 20 haloperidol and clozapine. patients with binding values between 7% and 47%. However, there was no clear relationship between the degree of receptor occu pancy and the presence of EPS. Conclusion: The findings suggest MATERIALS AND METhODS an exponential dose-response relationship between the daily dos Twenty patients with schizophrenia [Diagnostic and Statistical age of risperidone and the dopamine D2 receptor occupancy. The Manual ofMental Disorders (Third Edition-Revised) (DSM-III-R) blockade of specific striatal IBZMbinding found under therapy with (11)] (12 women, 8 men; age range 19—63yr) who were treated risperidone is between those of haloperidol and clozapine. The with mean daily doses of risperidone ranging from 0.029 to 0.128 dose-response curve for nsperidone, however, shows greater sim mg/kg body weight (2—8mg) were examined. Concomitant mcd ilarityto that of haloperidol. ication is listed in Table 1. No patient received any medication the KeyWords:iodine-123-iodobenzamideSPECT;schizophreniapa day before or the day of IBZM examination. In the case of tients; risperidone; extrapyramidal symptoms diazepam, the last medication was given at least I wk before the J Nuci Med I998 391138—1142 SPECT scan. None of these drugs is supposed to influence the dopaminergic system or the binding of IBZM to the dopamine D2 AL%dLccording to the “dopamine hypothesis― (1 ), positive symp receptor. The duration of illness varied between the first onset of toms of schizophrenia are due to hyperactivity of the dopami symptoms a few weeks before and more than I 0 yr before nergic system. The widely accepted concept is that occupancy examination. Five of the patients were also examined in a drug of dopamine D2 receptors is both essential and sufficient for a naive state. For assessment of EPS, the EPS rating scale was drug to have antipsychotic properties (2). As previously re applied by two psychiatrists blinded to the findings of the IBZM ported, dopamine D2 receptors can be studied in vivo using SPECT study. SPECT applying ‘23I-iodobenzamide(IBZM). IBZM is a ben For SPECT image acquisition, we used a triple-headed gamma zamide derivative developed for SPECT that has been shown to camera equipped with high-resolution fanbeam collimators (Prism bind reversibly with high affinity and high specificity to striatal 3000; Picker, Cleveland, OH). The acquisition parameters corn D2 receptors (3,4). The occupancy of striatal D2 receptors by prised a rotational radius of 13 cm or less, a 20% energy window various classic neuroleptics in schizophrenic patients has been centered on 159 keV, 120 projection angles over 360°and a 128 X demonstrated (2). By means of IBZM and SPECT, the occu 128 matrix with a pixel width of2. 11 mm in the projection domain. pancy of D2 receptors in patients receiving treatment with Data collection started 120 mm after injection and lasted for neuroleptics has been described in several studies (5,6). approximately 30 mm (45 sec/projection). The projection images were reconstructed by filtered backprojection. Then a three dimensional, counting rate-dependent, postprocessing filter (Wie Received May 2, 1997; revision accepted Oct. 9, 1997. For correspondence or reprints contact: Klaus Tatsch, MD, Department of Nuc@ar ncr filter) with a modular transformation function specific for 1231 Medicine, University of Mun@h,Marchioninistr. 15, 81377 Muruch, Germany. was applied. For uniform attenuation correction, Chang's first

1138 THEJOURNALOFNUCLEARMEDICINE•Vol. 39 •No. 7 •July 1998 TABLE I Patients' Mean Daily Dosages of Rispetidone and Background Corrected Values Expressed as Percentage Binding of Controls

dosage C @0 of nsperidone - BG)/BG C binding)BeforePatient no.Daily(mg/kgbodyweight)Concomitantmedication(S (% treatment0.000None119Before treatment0.000Doxepin108Before treatment0.000None94Before treatment0.000None92Before I treatment0.000None9110.029None6820.029None6330.037Diazepam

(occasionally)6340.039None3150.041None6360.041None5770.041Amitryptiline4180.042None4190.053None41100.058None44110.059None41120.067Doxepin56130.075None42140.093None21150.100None31160.100None28170.100None20180.100None7190.120None21200.128None33S0.00 0.02 0.04 0.06 O.O@ 0.10 0.12 0.14 Daily Dosage (mglkg b.w.)

FiGURE1. Dose-responserelationshipbetweensthatalD2receptoroccu pancy [(S - BG)/BGpercentage binding]and dally dose of nsperidone (mg/kgbody weIght).

headed camera, Prism 3000; Picker) and that used in the previously performed haloperidol/clozapine study (dual-headed camera, Rota II; Siemens, Iselin, NY; this system was replaced by the Picker system). Measurements in controls and a phantom were used to ensure that data obtained using both approaches were comparable. The control groups used for this study consisted of 10 healthy, age-matched subjects for each camera system, which were exam med to establish the threshold ofIBZM binding to the dopamine D2 receptor, above which subjects were considered to display normal binding. Two of them underwent imaging procedures on both —BG/BG= striatum —background/background. gamma cameras. Additionally, five patients of the risperidone treated group had baseline scans presenting with values consistent with the normal values established in the control group. The order method was used. Images were uniformly resliced by phantom used was a striataL/basal ganglia phantom developed by drawing a line connecting the antenormost aspect of the frontal the department of medical physics (University of Munich, Ger pole to the posteriormost aspect of the occipital pole, which many) containing four chambers (caudate right/left and putamen approximates the line connecting the anterior and posterior corn right/left) and a background chamber that could be filled sepa missures. To assess specific tracer uptake in the striatum, we used rately. The experiments were performed by filling the phantom the region of interest (ROl) technique. Mean specific activity in with different basal ganglia/background ratios and performing basal ganglia regions was calculated by subtracting the mean identical measurements on both cameras. The results of the counts per pixel in the frontal cortex as background (BG) from the phantom studies and for the two control subjects scanned on both mean counts per pixel in the basal ganglia region (5) and dividing cameras were used to confirm the comparability of the camera the result by the mean counts per pixel in the background [(S — systems. The expression of the main outcome measure as a BG)/BO}. Templates were used for defining the striatal ROIs. The percentage eliminates the different absolute ratios of both cameras, size and the shape of the templates were established and optimized since an individual control group was available. Therefore no using data from a control group. The nonspecific background corrections to the data were made. activity was estimated by drawing an ROI around the frontal cortex. In each patient, data were evaluated in the two consecutive RESULTS transverse slices showing the highest tracer accumulation in the Table 1 gives a summary of the subjects' medical character basal ganglia. Results are given as arithmetic mean of the two istics and IBZM SPECT findings. The dopamine D2 receptor slices. For statistical analyses, analysis of variance, regression binding of the ligand was reduced in all patients {[(S — analyses (least-squares method) and Student's t-test were used. BG)/BG] percentage binding = 7—68%}during therapy with Monoexponential fitting was applied to all data. All values were risperidone. All examinations of untreated patients showed normally distributed. Differences were considered statistically normal values. Figure 1 displays the (S —BG)/BG percentage significant when p < 0.05. binding values, reflecting dopamine D2 receptor binding in Data were compared to the results of a previously published relationship to the daily dosage of risperidone. The degree of study (6) of IBZM SPECT in patients receiving treatment with occupancy ofthe dopamine D2 receptors presented an exponen haloperidol and clozapine. tial dose-response relationship (r = —0.86;p < 0.0001 ). Figure All data were expressed as a percentage of normal binding with 2 shows similar data previously obtained in patients treated with a 100% value of{(S —BG)/BG] = 0.95 for the risperidone-treated haloperidol and clozapine. The remarkable linear dose-response group and 0.52 for the haloperidol- and clozapine-treated groups, curve for clozapine-treated patients reflects the lower D2 respectively, which were established by a control population. The receptor occupancy induced by this compound. Even at the difference from the normal values (0.95 versus 0.52) was due to the maximum doses of clozapine, D2 receptors in basal ganglia different technical equipment used in the rispendone study (triple remained unoccupied. A close inspection ofthe risperidone data

I0DINE-123-IBZM SPECT IN SCHIZOPHRENICPATIENTS•Dresel et al. 1139 120 pattern of 1231-IBZMbinding displayed remarkable similarity to that found in patients receiving typical neuroleptic treatment. Extrapyramidal symptoms were observed in eight patients @100 C showing (S —BG)/BG percentage binding values between 7% •0 and 47% (Fig. 3). However, there was no clear relationship .E 80 between the degree of receptor occupancy and the presence of EPS. These findings suggest that patients treated with risperi . 60 done display no direct relationship between striatal D2 occu pancy and the presence of EPS. Our previous study of haloper 0 idol-treated patients showed a threshold value ofIBZM binding to the D2 receptor of 40%, which means that patients usually @ 20 displayed EPS presenting a D2 receptor occupancy of 60% or higher. Similarly, patients receiving risperidone treatment 0 showing D2 receptor binding higher than 47% (occupancy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 <53%) exhibited no EPS. However, some of the rispendone treated patients presenting with binding values below this Daily Dosage (mg/kg b.w.) threshold also displayed no EPS. Figure 4 shows a typical FIGURE2. Dose-responserelationshipbetweenstnatalD2receptoroccu image in patients before and after treatment with different doses pancy [(S- BG@/BGpercentage binding]and dadydose of hakperidoland of risperidone. clozapine(mg/kgbody weight). DISCUSSION and similar data obtained using haloperidol and clozapine The findings of our study indicate an exponential dose suggests that the degree of specific striatal IBZM binding response relationship between the daily dosage of risperidone induced by risperidone is between that of patients treated with and the dopamine D2 receptor occupancy. The blockade of typical and atypical neuroleptics and is clearly lower than specific striatal IBZM binding is between those produced by binding in nonmedicated patients and controls. The slope of the haloperidol and clozapine. Extrapyramidal symptoms were curve was closer to that of haloperidol. Qualitatively, the observed in a remarkable subset of 40% of patients. However, there was no clear relationship between the degree of receptor occupancy and the presence of EPS. 120 Due to their propensity of inducing extrapyramidal side 0 EPMS effects mediated by dopamine D2 receptor occupancy, most 0)100C•DC& neuroleptics are usually referred to as typical antipsychotics. In contrast, atypical neuroleptics are those that have fewer or no extrapyramidal side effects in humans and do not produce catalepsy in animals (12). Clozapine was the first neuroleptic to meet these criteria and to have a strong antipsychotic potency (13). In our previous study (6), the occupancy of striatal D2 >@ receptors in patients receiving treatment with clozapine was significantly lower than that in patients taking typical high potency neuroleptics such as halopendol but was not lower than @;60:.. that in neuroleptic-free subjects. These results are consistent with SPECT studies reported by other groups (5,14,15). In 0 addition, Farde et al. (16) reported a range of 38%—63% D2 receptor occupancy in five patients taking clozapine using PET Risperidone Haloperidol Clozapine and 1‘C-. Similarly, the values of our patients were significantly lower than those of patients treated with conven FIGURE3.Rela@onshipbetweensthatalD2receptoroccupancy[(S- BG)tBG tional doses of typical antipsychotics. The occupancy of the D2 percentagebinding]and presentat@nof extrapyramidalsymptoms(EPMS). receptor has been suggested to mediate the antipsychotic effects

A ‘B ‘C

FIGURE4. lodine-123-IBZMSPECTrn ages of D2 receptor binding at equilib nurn. (A) Drug-naive schizophrenic pa tient (B)Schizophrenicpatient receMng treatment with risperkioneat dailydos age of 37 @Lg/kgbody wcight (C)The —.‘ f' - . @: same patienttreated withdailydosage of 100 pg/kg body wcight

1140 THEJOURNALOFNUCLEARMEDICINE•Vol. 39 •No. 7 •July 1998 of neuroleptics in cortical and/or limbic areas (14, 17,18). This model seems very unlikely to explain a dose-dependent receptor is the only receptor for which all classes of neuroleptics have occupancy, as this model would result in a specific binding of affinity in vitro (1 7,18). In contrast to classic antipsychotics, less than 0 at sufficiently high dosages. Previous in vivo clozapine has a higher affinity for the recently cloned dopamine functional imaging studies assessing the D2 occupancy of receptor subtypes D3, D4 and D5 (19—21), presumably located risperidone have consisted of reports of either single patients or in limbic and cortical areas, than for D2 binding sites. It also normal subjects not always receiving clinically relevant drug binds with high affinity to D1 as well as 5-HT2 and 5-HT3 regimens (28,31 ). Our study investigated the in vivo behavior serotonin receptors (22,23). Therefore, a complex interaction of of risperidone with respect to the D2 occupancy and the clozapine with these receptor classes may be responsible for the incidence of EPS. neuroleptic effect. Moreover, the locations of these receptors in Some patients received concomitant medication. According limbic and cortical areas agree with the low prevalence of to the literature, there is no evidence for possible influence of extrapyramidal side effects mediated by nigrostriatal neurons. these drugs on the binding of IBZM to the dopamine D2 For typical high-potency neuroleptics, such as haloperidol, a receptor (32). Two of these belong to the group of antidepres dose-dependent occupation of striatal D2 binding sites was santS known as tricyclic psychotherapeutic agents. The mech reported in other studies using PET (24) and IBZM SPECT (5). anism of these drugs is not definitely known. They are not The findings of our previous study confirmed these results in a central nervous system stimulants or monoamine oxidase inhib larger patient group (6). Our findings are consistent with those itors. The current hypothesis is that the clinical effects are due of a study using ‘8F-methylspiperone (25), which reported a 40% occupancy of striatal D2 receptors in subjects taking low to the influence on the reuptake of norepinephrine. The other doses of halopendol. It can be concluded that relatively low drug that has been occasionally applied is diazepam. Its doses occupy a high proportion of D2 receptors, as reflected by influence on the dopaminergic system has not been described. the steep decline of the curve in patients treated with haloper However, none of our patients received medication on the day idol (5,6,14,24). before or the day of the IBZM examination. Risperidone is a recently licensed neuroleptic that was The characterization of high levels of D2 occupancy in vivo introduced to induce fewer EPS than typical neuroleptics such are in clear contrast with the low incidence of EPS reported in as halopendol. However, in vitro binding studies of rispendone recent clinical trials with this drug (31,33 ). In our patient group, suggest a high affinity for D2 receptors and potent 5-HT2- EPS were found in 40% of the patients, which is less than the blocking properties (26,27). In a PET study using 1‘C-raclo percentage obtained using halopendol. These findings are in pride, 50% occupancy of stnatal D2 receptors was reported in line with results reported in the literature (34). The mechanisms volunteers receiving 1 mg of risperidone (28). responsible for the low incidence of EPS are still unclear. In Although using ‘231-IBZMSPECT to investigate dopamine studies of typical neuroleptics such as haloperidol, it has been D2 occupancy does not provide absolute quantitative measures shown that EPS are related to the level ofdopamine D2 receptor of tracer binding to dopamine D2 receptors, as is possible with occupancy (5,6, 16). However, as previously described, the PET, this method has proven to be valid and reproducible in relationship between dopamine D2 receptor occupancy and EPS assessing D2 occupancy in normal volunteers, drug-naive pa is complex, which may account for the fact that very high doses tients with schizophrenia and patients receiving different of haloperidol (10 times higher than those used in our study) classes of neuroleptics (6, 15,29,30). Furthermore, PET studies may in some cases not produce EPS (35). Contrary to typical using semiquantitative approaches and relative measures have neuroleptics, new generation neuroleptics such as risperidone been shown to reflect the results obtained with absolute quan showed an additional, even higher affinity to 5-HT2 receptors tification (28). Our results clearly indicate that ‘231-IBZM than that to dopamine D2 receptors (36). This property is SPECT can distinguish between groups of patients taking similar to the 5-HT2 affinity of atypical neuroleptics such as typical neuroleptics and neuroleptic-free patients. Thus, the clozapine; however, the D2 receptor affinity of clozapine is occupancy of central dopamine receptors, which is thought to much less. In the case of nsperidone, the crucial factor be the essential pharmacological mechanism in the action of preventing the development of significant EPS may indeed be neuroleptics (29), can be visualized with IBZM SPECT imaging. the high 5-HT2-blocking potency of the drug (10). It has been The moderate degree of receptor occupancy with low doses suggested that concomitant blocking of 5-HT2 receptors may of risperidone predicts that high levels of D2 receptor occu exert a protective effect against EPS induced by D2 antagonism pancy should be found at clinical doses. In a study of five (8,26). The reported 5-HT2 versus D2 potency ratio is about 20 patients treated with daily doses up to 12 mg (31 ), mean (S — BG)/BG ratios of 0.23 (normal value in this study is 0.68) were (37). The combination of both receptor occupancies and the found. Indeed, our study confirmed that patients with the overblockade of 5-HT2 receptors compared to D2 receptors is highest daily doses of risperidone (8 mg) presented with the believed to reduce the incidence of EPS in patients treated with lowest ratios. These results suggest high levels of dopamine D2 risperidone. Consistent with the findings of our study, the in receptor occupancy with risperidone, indistinguishable from the vivo and in vitro dopamine D2 receptor occupancy of risperi patterns found in patients taking low dosages of typical neuro done reported by Schotte et al. (37) was closer to that of typical leptics and significantly higher than those in clozapine-treated neuroleptics (haloperidol) and higher than that of clozapine. patients. However, when comparing the dose-response relation This would suggest that the EPS benefits of risperdone cannot ship, the curve of risperidone fits between the curve of be explained by low D2 binding, but may indeed be related to haloperidol, with its steep decline, and the curve of clozapine. its high 5-HT2 affinity. However, the emergence of EPS at For the haloperidol and risperidone data, the monoexponential higher levels ofD2 receptor occupancy in this study and in other fitting gives the most appropriate plausible correlation coeffi publications (28,34) would suggest that risperidone's high

. cient. The rather low occupancy of dopamine D2 receptors by 5-HT2 affinity provides only a relative protection from EPS. clozapine fits to a linear as well as to a monoexponential model. The findings suggest that high levels of D2 receptor occupancy However, the exponential fit gives the strongest correlation do not necessarily induce EPS and therefore do not prevent a fitting, and from the biological point ofview, a linear regression neuroleptic drug from being classified as atypical (31).

IoDm@E-123-IBZMSPECT m@SCHIZOPHRENICPATIENTS•Dresel et al. 1141 CONCLUSION treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry l992;49:538—544. Our findings suggest an exponential relationship between 17. Creese I, Burt DR. Snyder 5. Dopamine receptor binding predicts clinical and striatal D2 receptor occupancy and the total daily dose of pharmacological potencies of antischizophrenic drugs. Science 1976;l92:48I—483. risperidone in a larger number ofpatients using a wide range of 18. Peroutka SJ, Snyder SH. Relationship of neuroleptic drug effects at brain dopamine, serotonin, a-adrenergic, and histamine receptors to clinical potency. AmJ Ps@vchiatrv dosages. We clearly showed that risperidone, which was l980;l37:l518—l522. thought not to occupy dopamine D2 receptors to a large extent, 19. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz i-C. Molecular cloning inhibits IBZM binding more than expected. However, even and characterization of a novel dopamine receptor (D3) as a target of neuroleptics. Nature l990;347:l46—151. patients presenting with a receptor occupancy above a threshold 20. Van Tol HHM, Bunzow JR. Guan HC, et al. Cloning of the gene for the human D4 of 53% were EPS free. A relationship between the presence of receptor with high affinity for the antipsychotic clozapine. Nature 199l;350:6l0—6l4. EPS and the individual dosage was not verified. Compared to 21. Sunahara RK, Guan H-C, O'Dowd BF, et al. Cloning of the gene for the human dopamine D5 receptor with higher affinity for dopamine than D, . Nature 1991350: our previous studies of the typical neuroleptic haloperidol and 614—619. the atypical neuroleptic clozapine, the dose-response curve of 22. Coward DM, Imperato A, Urwyler S. Biochemical and behavioural properties of dopamine D2 receptor binding during treatment with risperi clozapine. Psychopharmacology 1989;99:6—l2. 23. Meltzer HY, Matsubara 5, Lee JC. 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1142 THEJOURNALOFNUCLEARMEDICINE•Vol. 39 •No. 7 •July 1998