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A New Framework for Investigating Antipsychotic Action in Humans: Lessons from PET Imaging S Kapur

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A New Framework for Investigating Antipsychotic Action in Humans: Lessons from PET Imaging S Kapur Molecular Psychiatry (1998) 3, 135–140 1998 Stockton Press All rights reserved 1359–4184/98 $12.00 PERSPECTIVE A new framework for investigating antipsychotic action in humans: lessons from PET imaging S Kapur Schizophrenia Division and the PET Centre, The Clarke Institute of Psychiatry, Department of Psychiatry, University of Toronto; Rotman Research Institute, Baycrest Centre, University of Toronto With a decade of neuroreceptor imaging of antipsychotics behind us, this article attempts to synthesise what has been learnt about the mechanism of action of antipsychotics using these techniques. The data show that: (i) the ‘typical’ antipsychotics bind mainly to the dopamine D2 receptor, and that 60–80% D2 occupancy may provide optimal antipsychotic response with little extrapyramidal side effects; (ii) all the clinically available ‘atypical’ antipsychotics show a higher occupancy of the 5-HT2 than D2 receptors; (iii) however, these ‘atypical’ antipsy- chotics differ in their D2 occupancy. The D2 occupancy of risperidone is within the typical range (ie Ͼ 60%) while that of clozapine is clearly lower (Ͻ60%); (iv) antipsychotics with com- bined 5-HT2/D2 antagonism lose some of their ‘atypical’ properties if used in doses where Ͼ their D2 occupancy is too high ( 80%). Based on these data a framework is suggested wherein antipsychotics may be classified on the basis of their D2 and 5-HT2 occupancy in patients at steady state while taking clinically relevant doses. Within this framework typical antipsy- chotics are classified as ‘high-D2’, risperidone as ‘high-D2 high-5HT2’ and clozapine as a ‘low- D2 high-5HT2’ antipsychotic. The justification, limitations and the value of this framework in understanding and investigating newer antipsychotics is discussed. Keywords: schizophrenia; antipsychotics; dopamine receptors; serotonin receptors; positron emis- sion tomography Introduction D2 receptors and found that typical antipsychotics occupied 70–89% D receptors at conventional clinical It has been a decade since the first studies1,2 of the 2 doses. Moreover, patients with extrapyramidal side- effects of antipsychotics on brain receptors were effects (EPS) had, on average, higher D occupancy reported. Much has been learnt since. The purpose of 2 than those who did not exhibit EPS (82% vs 72%). This this article is to synthesize this information. This is not relationship was further supported by Nordstrom et al6 a comprehensive review of PET data on this subject. who found that those with greater than 60% D occu- Instead it represents a selective analysis of the extant 2 pancy showed much better antipsychotic response data with a view to develop a theoretical perspective than those with occupancies below 60%. These data and a clinical understanding of the role of the dopa- suggest that there may be a therapeutic window, per- mine D and serotinin 5-HT receptors in the treatment 2 2 haps between 60% and 80% D occupancy, which may of schizophrenia. 2 yield adequate antipsychotic response with low or minimal EPS. Typical antipsychotics, D2 occupancy and clinical In a clinical context, it has been shown that low correlates doses of oral haloperidol, 1–5 mg day−1 (plasma levels of 0.5–5.8 ng ml−1) lead to occupancies ranging from 50 It has been known for almost two decades that antipsy- − to 88%; and that 2 mg day 1 of haloperidol may be suf- chotic effects and extrapyramidal side effects (as well ficient to get most patients into the putatively thera- as catalepsy in animals) are related to the dopamine D 2 peutic 60–80% occupancy range.7 To test the clinical blocking properties of antipsychotics.3,4 However, validity of this, seven patients, all suffering from a first prior to the advent of PET imaging it was not possible episode of schizophrenic illness, were treated with hal- to observe any of these relationships at a receptor level − operidol 2 mg day 1 in an open clinical-PET investi- in vivo in humans. Farde et al5 reported the first sys- gation.8 The average D receptor occupancy was 67% tematic study of the action of antipsychotics on in vivo 2 and significant improvement in positive as well as 8 negative symptoms was observed. This clinical-D2 occupancy correlation fits rather nicely with McEvoy Correspondence: Dr S Kapur, PET Centre, The Clarke Institute of 9 Psychiatry, 250 College Street, Toronto, ON, Canada M5T 1R8. et al who applied a clinical ‘neuroleptic threshold’ E-mail: kapurȰclarke-inst.on.ca technique to determine the minimal effective dose. The Received 28 April 1997; revised and accepted 24 July 1997 median threshold dose for the first episode patients PET imaging of antipsychotics S Kapur 136 Ͼ was 2.1 mg of haloperidol—and the addition of an 80% D2 occupancy using SPECT). Thus at effective extra 5–10 mg day−1 of haloperidol did not significantly doses (between 200–400 mg day−1)22 clozapine occu- augment their clinical response, but did increase the pies significantly fewer D2 receptors than are occupied incidence of EPS. Several recent studies by Stone et by typical antipsychotics and certainly fewer than al,10 Janicak et al11 as well as Ortega-Soto et al12,13 all those associated with EPS. point to the effectiveness of low dose antipsychotics Risperidone, like clozapine, exhibits high levels of −1 (2–5 mg day of haloperidol or equivalent) and uni- 5-HT2 occupancy. However, risperidone’s D2 occu- formly show that higher doses (10–50 mg day−1) pancy is clearly higher than that of clozapine.23–25 increase the incidence of EPS-related side-effects with- Kapur et al25 have shown that, on average, 2 mg day−1 out an appreciable change in clinical response. of risperidone occupied 66% of D2 receptors, Even with optimal dosing, a significant number of 4 mg day−1 occupied 73% while 6 mg day−1 occupied patients (estimated between 20–50%) do not respond 79%. While most patients with risperidone did not satisfactorily to treatment with D2 blockers. The cause experience EPS, those who did experience EPS had a of this non-response is not known, but non-responders much higher D2 occupancy than those who did not 14,15 ± ± show no difference in their D2 occupancy profiles. (79% 4% vs 68% 5%). Thus risperidone’s high lev- This has led to the suggestion that non-responders to els of 5-HT2 occupancy (whatever its other benefits) D2 occupancy may reflect a biologically distinct subset cannot provide absolute protection from EPS once D2 of the illness.14,15 In fact Pilowsky et al16 show that blockade is near complete.25,26 some patients who do not respond despite high and The putatively negative effects to too much D2 block- adequate D2 occupancy, respond to much lower D2 ade can also be observed in the multi-centre studies occupancy with clozapine (which affects several recep- which compared 2–16 mg day−1 of risperidone with −1 27,28 −1 tor systems in addition to D2). Even those who do 10–20 mg day of haloperidol. Six mg day of ris- respond to the D2-mediated mechanism of response peridone was numerically and statistically superior to usually show less than satisfactory improvement in haloperidol in terms of positive, negative and EPS syn- negative symptoms and cognitive impairment. These dromes. However, beyond 6 mg day−1, the positive and limitations of the typical antipsychotics (some patients negative symptom response decreased and EPS are refractory, many get EPS, and negative and positive increased, such that risperidone 10–16 mg day−1 was symptom improvement is limited) necessitated the statistically indistinguishable from haloperidol. Doses development of ‘atypical’ antipsychotics. of risperidone beyond 6 mg day−1 give greater than 25,29 80% D2 occupancy. Thus, it would seem that push- ing D occupancy to saturation, in atypical drugs like Atypical antipsychotic, 5-HT and D occupancy, 2 2 2 risperidone, may not only diminish their EPS superior- and clinical correlates ity, but may also decrease their superiority on positive While there is no consensus on how to define an atypi- and negative symptoms. Therefore, it is not sufficient cal antipsychotic, most authorities agree that clozapine that a drug display the ‘right 5-HT2/D2 affinity ratio’ in (and more recently risperidone, olanzapine and the test tube.17,18 It is imperative that the drug be used sertindole) are ‘atypical’. All four of the above agents in humans in doses where D2 occupancy is not satu- are distinguished from typical antipsychotics by one rated.25 pharmacological commonality: a higher affinity for the 5-HT2 as opposed to D2 dopamine receptor in vitro as Beyond the typical/atypical dichotomy: towards a well as ex vivo in animals.17,18 Since reliable neuroim- new framework aging data in humans are available only for clozapine Until recently, clozapine was the only ‘atypical’ anti- and risperidone, this section focuses on these two psychotic but several new antipsychotics are available atypical antipsychotics. now. They all differ from the typical antipsychotics, A comprehensive PET study of the receptor profile but it is increasingly becoming evident that these of clozapine shows that the D2 occupancy in patients newer antipsychotics may not replicate all of cloza- −1 treated with 125–600 mg day of clozapine varied pine’s features. One can classify these drugs on the from 20–67%, while at these doses the 5-HT2 occu- basis of their in vitro pharmacological character- 19 pancy is always greater than 80%. No patient on cloz- istics,30–32 their neurophysiological actions,33 their apine demonstrated D2 occupancy in the range that is gene-induction profiles34 or their actions in animal likely to produce EPS (ie 80% or greater). We find simi- models.35 However, all these schemes are based on pre- lar results in a series of nine patients whose doses clinical characteristics of these medications.
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