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Antipsychotic Drugs Which Elicit Little Or No Parkinsonism Bind More Loosely

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Antipsychotic Drugs Which Elicit Little Or No Parkinsonism Bind More Loosely Molecular Psychiatry (1998) 3, 123–134 1998 Stockton Press All rights reserved 1359–4184/98 $12.00 PERSPECTIVE Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors P Seeman1,2 and T Tallerico1 Departments of 1Pharmacology and 2Psychiatry, University of Toronto, Toronto, Canada M5S 1A8 This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70–80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as meas- ured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70–80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70–80% occu- pancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70– 80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkin- sonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs. Keywords: antipsychotics; clozapine; atypical neuroleptics; risperidone; D2 receptor occupancy 1. Apparent low occupancy of dopamine D2 0% and °50% of brain dopamine D2 receptors, as mea- receptors by clozapine sured by a variety of radioligands using either positron tomography1,2,8–13 or single photon tomography.14–19 Antipsychotic drugs, when given at clinically effective Although the apparently low occupancy of D2 by doses, generally occupy between 70% and 80% of clozapine might suggest that D2 may not be the major brain dopamine D2 receptors in patients,1–7 as meas- antipsychotic target for clozapine (because clozapine ured in the human striatum (ie the caudate nucleus binds to many other neurotransmitter receptors)20 it is and/or the putamen). Clozapine, however, has consist- necessary to analyse these low occupancy data in the ently been an apparent exception. For example, in light of recent evidence showing that the occupancy of patients taking therapeutically effective antipsychotic a receptor by a drug depends on the radioligand used doses of clozapine, this drug only occupies between to measure that receptor.21–26 This latter finding shows that the occupancy is higher when radioligands with higher dissociation constants are used. Correspondence: P Seeman, Pharmacology Department, Medical Using this latter finding, therefore, one objective in Science Building, 8 Taddle Creek Road, Toronto, Ontario, Canada M5S 1A8 this mini-review was to determine indirectly the occu- Received 23 April 1997; revised 15 and 21 July 1997; accepted pancy by clozapine of brain dopamine D2 receptors 26 August 1997 that must in fact be taking place in vivo in patients Atypical antipsychotics bind loosely to D2 receptors P Seeman and T Tallerico 124 being treated with clozapine in the absence of any pine, for example, has a K of 35–59 nM for D2 using radioligand. This analysis indicates that clozapine, at [3H]raclopride,22 compared to a value of 44 nM for the therapeutic doses, occupies high levels (of the order radioligand-independent dissociation constant (Table of 70–80%) of dopamine D2 receptors in the striatum, 1). Similarly, haloperidol has a K of 0.5–0.6 nM, using similar to the occupancies found with therapeutic the very large volumes,22 compared to the radioligand- doses of other antipsychotic drugs, and that clozapine independent dissociation constant of 0.4 nM in may possibly occupy even higher levels in the limbic Table 1. Hence, the large-volume method and the radi- regions where the endogenous synaptic dopamine is oligand-independent method provide data which con- lower than that in the striatum. firm one another. 2. Potencies of antipsychotic drugs at dopamine 3. Clinical antipsychotic potencies correlate with D2 receptors true dissociation constants at D2 The occupancy of receptors can be determined directly These antipsychotic drug dissociation constants, by radioligand tomography or indirectly by measuring which are independent of the radioligand used the concentration, C, of the antipsychotic drug in the (Table 1), correlate with the antipsychotic doses used spinal fluid. Using the latter method, the percent of clinically (Figure 1). This correlation agrees with pre- receptors occupied, f, is equal to C/(C + K), where K is vious work.29–32 the dissociation constant (or inhibition constant) of the Of the many antipsychotic drugs shown in Figure 1, antipsychotic drug at the D2 receptor. only chlorpromazine and thioridazine deviate signifi- The concentration method, therefore, provides an cantly from the overall correlation. The deviations for independent estimate of receptor occupancy by anti- these two drugs, however, disappear when the spinal psychotic drugs. The free concentrations of antipsy- fluid concentrations of the various antipsychotic drugs chotics in the cerebrospinal fluid and in the plasma are considered (next section). water (ie, not bound to plasma proteins) have pre- viously been reviewed,27 although an important 4. Therapeutic levels of antipsychotic drugs revision to the data for clozapine is added below. occupy high levels of brain dopamine D2 In order to derive the clinical receptor occupancies receptors from the antipsychotic concentrations, it is necessary to have accurate K values, as indicated in the above The occupancy of brain dopamine D2 receptors, under equation for the occupancy, f. These K values, how- clinically therapeutic conditions, can now be ever, differ considerably between laboratories for a var- indirectly determined from the antipsychotic drug iety of technical reasons.27,28 Hence, it is essential to average concentrations in the spinal fluid and using have K values for all antipsychotic drugs from a single the radioligand-independent dissociation constants in laboratory using standard conditions. Table 1. As noted above, recent evidence shows that the anti- The dissociation constant, K, in Table 1 is defined as psychotic occupancy or the antipsychotic K (which is the antipsychotic concentration required for 50% occu- the concentration for 50% occupancy of a receptor) pation of the receptor in the absence of dopamine or depends on the radioligand used to measure that recep- any other ligand. In reality, however, because the anti- tor.21–26 For example, antipsychotic drugs which bind psychotic drug must compete with dopamine within loosely (ie, with high K) to the receptor are less able the synaptic space, the antipsychotic concentration to to compete against tightly bound radioligands (ie, with block 50% of the receptors in the presence of dopa- low K). mine (C50%) will be higher than that in the absence of Hence, it has been necessary to obtain true dis- dopamine, in accordance with the equation = × + sociation constants which are independent of the radi- C50% K [1 D/D2High], where D is the effective dopa- oligand used. This has now been done for many anti- mine concentration in the synapse and where D2High is psychotic drugs at human cloned dopamine D2, D3, D4 the dissociation constant of dopamine at the high- and serotonin 2A receptors, and a list of these values affinity state of the dopamine D2 receptor. is given in Table 1 (summarized from Refs 21–26). Although the effective concentration of dopamine in Although the technical explanation for the apparent the synapse is not known, it is considered to be any- dependence of the antipsychotic dissociation constant where between 1 nM and 45 nM. The basal level of on the radioligand is not known, detailed experiments synaptic dopamine in the rat nucleus accumbens has have shown that it is not a result of radioligand been estimated to be 4 nM.35 At a firing frequency of depletion.21 Although most laboratories
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