ORIGINAL ARTICLE A Positron Emission Tomography Study of Quetiapine in Schizophrenia A Preliminary Finding of an Antipsychotic Effect With Only Transiently High Dopamine D2 Receptor Occupancy Shitij Kapur, MD, PhD, FRCPC; Robert Zipursky, MD, FRCPC; Corey Jones, BSc; C. S. Shammi, MD, FRCPC; Gary Remington, MD, PhD, FRCPC; Philip Seeman, MD, PhD Background: Quetiapine is a new atypical antipsy- lactin level elevation noted at baseline. It achieved chotic medication. As such, relatively little has been pub- these results with minimal (0%-27%) D2 occupancy 12 lished regarding its in vivo effects at the dopamine type hours after the last dose. Study of the additional sub- 2(D2) and serotonin type 2a (5-HT2a) receptor systems. jects revealed that quetiapine does give rise to tran- The following study was undertaken to explore these ef- siently high (58%-64%) D2 occupancy 2 to 3 hours fects across the clinical dose range and relate this infor- after a single dose that then decreases to minimal lev- mation to its clinical profile. els in 12 hours. Methods: Twelve patients with schizophrenia were ran- Conclusions: Quetiapine shows a transiently high D2 domly assigned to doses of 150 to 600 mg/d (n=3, at 150, occupancy, which decreases to very low levels by the 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of end of the dosing interval. Quetiapine’s low D2 occu- treatment, D2 and 5-HT2a occupancy were measured us- pancy can explain its freedom from extrapyramidal ing positron emission tomography (PET) imaging, 12 to symptoms and prolactin level elevation. The data sug- 14 hours after the last dose. Clinical efficacy and ad- gest that transient D2 occupancy may be sufficient for verse effect ratings were obtained at baseline, at the time its antipsychotic effect. Future studies controlling for of PET scanning, and at 12 weeks. Two additional pa- nonpharmacological effects as well as activities on tients were included to examine the effects of the drug 2 other receptors will be necessary to confirm this sug- to 3 hours after last dose. gestion. Results: Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and pro- Arch Gen Psychiatry. 2000;57:553-559 LL ANTIPSYCHOTICS (typi- pancy also predicts the 2 main adverse ef- cal as well as atypical) fects: extrapyramidal symptoms (EPS) and show affinity for type 2 do- prolactin level elevation. Extrapyramidal pamine (D2) receptors in symptoms are observed when D2 occu- vitro; this measure is the pancy rises above 75% to 80% of striatal best in vitro predictor of the clinical dose D2 blockade, even with the atypical anti- A 1,2 5,6 for antipsychotic response. For ex- psychotics. While it is not possible to ample, the relative in vitro affinities of ris- measure pituitary D2 receptor occupancy peridone, olanzapine, and clozapine for the directly, using striatal D2 occupancy as a D2 receptor are the ratios −3:17:150:310 surrogate, prolactin level elevation can be nmol/L, with affinity decreasing from ris- predicted.7,8 This suggests that measur- 3 peridone to quetiapine. As predicted by ing the D2 occupancy of antipsychotics can From the Schizophrenia this, their clinical doses also share a simi- reveal useful information about their Program (Drs Kapur, Zipurksy, lar relationship: risperidone, 3 to 6 mg/d; mechanism of action. Jones, Shammi, and Remington) olanzapine, 10 to 20 mg/d; clozapine, 250 Many of the current atypical antipsy- and PET Centre (Drs Kapur to 450 mg/d; and quetiapine, 300 to 600 chotics block serotonin type 2a (5-HT2a) and Jones), the Clarke Division 9,10 mg/d. Lending further support for the role receptors in addition to D2 receptors. of the CAMH, Department of D blockade in antipsychotic action, However, 5-HT antagonism is not nec- of Psychiatry (Drs Kapur, 2 2a Zipursky, Shammi, Remington, studies show that the clinically pre- essary for atypical antipsychotic action, and Seeman), and the scribed doses of most typical and atypi- since remoxipride and amisulpiride are Department of Pharmacology, cal antipsychotics (with the exception of atypical antipsychotics without any rel- 11-13 University of Toronto, Toronto, clozapine) give rise to 65% to 90% D2 re- evant 5-HT2a antagonism. It has been 4-6 Ontario (Dr Seeman). ceptor blockade. The D2 receptor occu- suggested that 5-HT2a antagonism may en- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, JUNE 2000 WWW.ARCHGENPSYCHIATRY.COM 553 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS noncompliance and 1 because of inability to complete the PET scan) and were replaced by random assignment. When the initial results showed very low D2 occupancy PATIENTS despite adequate plasma levels, it was decided to recruit 2 additional subjects to investigate the time course of occu- This study was approved by the Human Subjects Review Com- pancy. Two subjects who were receiving routine clinical mittee of the University of Toronto and all subjects pro- treatment with quetiapine, but met all inclusion and ex- vided written consent prior to participation. Patients were re- clusion criteria listed above, were recruited for this com- cruited from the inpatient units and outpatient clinics of the ponent. Both the patients had been receiving quetiapine Schizophrenia Division of the Centre for Addiction and Men- for more than 1 month and were at multiple-dose steady tal Health, a university-affiliated psychiatric facility. Pa- state; one (aged 24 years and male) was receiving 400 mg tients were included if they were voluntary and competent twice daily; while another (aged 29 years and male) was to consent to treatment and research, aged between 18 and receiving 450 mg every night. 45 years, and carried a clinical diagnosis of schizophrenia con- firmed using a DSM-IV18 criteria checklist by a trained re- STUDY DOSING AND CLINICAL ASSESSMENTS search rater (C.J.). Patients were excluded if they suffered from a major medical or neurological illness, met DSM-IV criteria Patients enrolled in the study went through a 1- or 2-day wash- for substance abuse in the last 3 months or substance depen- out and were then titrated to their assigned dose of quetiap- dence in the last 6 months, or had received a depot antipsy- ine. The 150-mg group achieved their target dose in 3 days, chotic medication in the 12 months prior to the study.19 All the 300-mg/d group in 4 days, the 450-mg/d group in 6 days, patients agreed to abstain from use of alcohol or illicit psy- and the 600-mg/d group in 7 days. Patients were then held choactive drugs during the 12-week study period; this was at their assigned dose for at least a period of 14 days and were monitored clinically, but was not confirmed using any blood scanned between days 21 and 28 of quetiapine treatment. or urine tests. Subjects were not involved in any specific non- Given the short half-life of quetiapine (approximately 6 hours), pharmacological therapies aside from routine clinical care. all patients should have been at steady state plasma concen- Patients were allowed access to benzodiazepines and anti- trations at the time of the PET scan. After the PET scan, the parkinsonian medication as deemed clinically necessary; no patients reverted to flexible dosing (150-600 mg/d) and were subjects required antiparkinsonian treatment. evaluated with structured ratings for another 8 weeks. The patients were assigned to treatment, using a ran- To determine clinical outcome, each of the patients dom sequence generated by computer, stratified to pro- was rated on the Positive and Negative Syndrome Scale vide 3 patients at each of the 4 doses: 150 mg/d (75 mg twice (PANSS)20 and a Clinical Global Impression Scale (CGI) daily), 300 mg/d (150 mg twice daily), 450 mg/d (225 mg for severity of illness and for improvement with treat- twice daily) and 600 mg/d (300 mg twice daily). All sub- ment.21 Adverse effects were rated using the Barnes Aka- jects who completed the PET scans are included in the thisia Scale22 and the Simpson Angus Rating Scale.23 These analysis. Three original subjects discontinued the study scales were administered to all the patients by a single trained before the PET scans (2 of them because of protocol rater (C.J.) who has previous experience as well as hance antipsychotic action and may delay the onset of RESULTS 9 EPS. For this reason, measuring the 5-HT2a occupancy of atypical antipsychotics, particularly in relationship to CLINICAL CHARACTERISTICS 6 their D2 occupancy, is of significant interest. Quetiapine is a new atypical antipsychotic that shows Twelve patients completed the controlled part of the a preference for the 5-HT2a as compared with the D2 recep- study. The sample consisted of 9 men and 3 women, tor in vitro and ex vivo in animal studies.3,14 In clinical tri- with a mean ± SD age of 29.6±6 years (age range, als it is significantly superior to placebo15,16 and comparable 21-40 years). Ten of the patients were outpatients and with typical antipsychotics.16,17 While there is conflicting evi- 2 were inpatients. The average number of previous dence regarding its efficacy in low doses (150-250 mg/d),15,16 admissions was 1 (range, 0-4 admissions). The quetiapine is significantly superior to placebo at doses of mean±SD duration of illness since first psychotic 300 mg/d or more,15,16 and equivalent to haloperidol16 and break was 93±76 months. chlorpromazine17 in large multicenter trials. At the same time, quetiapine’s incidence of EPS and prolactin level el- DRUG LEVELS AND RECEPTOR OCCUPANCY evation is indistinguishable from that of placebo.15-17 Based on these findings, we were interested in the Patients showed a dose-dependent increase in plasma lev- following questions: (1) Does quetiapine produce D2 re- els of quetiapine: mean±SD, 29±4 ng/mL when given 150 ceptor blockade at clinical doses? (2) Does it have a promi- mg/d; 50±28 ng/mL when given 300 mg/d; 172±111 nent effect on 5-HT2a receptors? and (3) What is the re- when given 450 mg/d; and 201±113 when given 600 mg/d lationship between its receptor occupancy and its clinical (F1,10=10.67, r=0.71, P=.008).