BRITISH JOURNAL OF PSYCHIATRY "2001), 179, 503^508

structures. In order to compare four atypi- Extrastriatal and striatal D22 dopamine receptor cal antipsychotics with a traditional mol- blockade with haloperidol or new antipsychotic ecule at the recommended dose ranges for therapeutic antipsychotic effect, we studied the binding of the reference compound drugs in patients with schizophrenia* haloperidol K ˆ1 nM) and that of four i D2† atypical antipsychotics ± risperidone K ˆ © i D2† X.XIBERAS,J.L.MARTINOT,L.MALLET,E.ARTIGES,C.LOC'H,B.MAZIEX. XIBERAS, J. L. MARTINOT, L. MALLET, E. ARTIGES, C. LOC'H, B. MAZIERERE 3 nM),3nM),clozapine K ˆ125 nM), amisul- i D2† and M. L. PAILLEPAILLERE-MARTINOT© RE-MARTINOT pride K ˆ3.4 nM and K ˆ3.5 nM)3.5nM) i D2† i D2† and olanzapine K ˆ11 nM) Chivers etet i D2† alal, 1988) ± in patients with schizophrenia treated with these compounds.

Background Bothtraditional and Dopamine D22 receptor blockade is thought atypical antipsychotics have been to mediate antipsychotic action. In vivoInvivo METHOD studies in medicated patients have shown hypothesised to be effective in that treatments with traditional antipsy- Subjects schizophrenia throughthroughlimbic limbic and cortical chotic compounds such as haloperidol Nineteen patients with DSM±IV American dopamine receptor blockade. DD22 consistently induce 70±80% occupancy of Psychiatric Association, 1994) schizophrenia the striatal D receptors Martinot et aletal,, Aims Toinvestigatethishypothesiswith 22 16 males, 3 females, mean ageˆ32 years,32years, 1990; NordstroNordstromÈ m et aletal, 1993). Further- s.d.s.d.ˆ7) treated with haloperidol nnˆ4),4), the D /D -selective positron emission 22 33 more, high levels of D22 receptor occupancy risperidone nnˆ3), clozapine nnˆ3), amisul-3),amisul- tomography PET) probe [7676Br]-FLB457. in the striatumstriatum are associated with higher pride nnˆ5) or olanzapine nnˆ4) were4)were risk of extrapyramidalextrapyramidal side-effects Farde included Table 1). They were treated with MethodMethod PETscans were performed on et aletal, 1992). At variance with traditional daily dosages matching the recommended 66controlsand18patientswith controls and18 patients with compounds, atypical antipsychotics such ranges for antipsychotic effect. For haloper- schizophrenia treated with haloperidol or as clozapinehave a low tendency to induce idol this range was 3±20 mg/day Editions extrapyraextrapyramidalmidal side-effects Moller, 2000). with risperidone, clozapine, amisulpride du Vidal, 1993; Zimbroff et aletal, 1997); for This maymayThis be consistent with the lower inin risperidone, 6±12 mg/day Kasper, 1998; or olanzapine. vivovivo DD22 striatal blockade reported with NybergNyberg et aletal, 1999); for clozapine, 200± the usual doses of clozapine Farde et aletal,, ResultsResults The D dopamine receptor 400 mg/day Fitton & Heel, 1990); for ami-ami- 22 1992). Whereas the nigro-striatal dopa- sulpride, 200±1200 mg/day Coukell et aletal,, blockadeblockadewashighinthetemporalcortex was high in the temporal cortex minergic pathways appear to be involved 1996); and for olanzapine, 5±20 mg/day with both haloperidol and atypical in extrapyramidal side-effects, models of Kasper, 1998). Patients were scanned 18±18± antipsychotics.The atypicals, however, the antipsychotic mechanism of action in- 20 h after the last evening dose of the anti- volve extrastriatal cerebral structures such psychotic, in order to avoid the peak induced a significantlysignificantlylower lower D 22 bindingbinding as theasthemeso-cortico-limbic pathways Moore plasma concentration following the drug index than haloperidolinthehaloperidol in the thalamus and et aletal,,1999). Therefore, the D22 receptorreceptor dose intake. All patients were medicated in the striatum. blockade by antipsychotic drugs in extra- for at least 15 days, which is much longer striatal structures may be one of the than the five half-lives necessary to reach Conclusions Results suggest that mechanismsthat account for the anti- the steady state for plasma antipsychotic cortical DDcortical 22 dopamine receptors are a psychotic effect, as suggested by earlier concentration. Exclusion criteria included common target of traditional and atypical single photon emissiontomography studies neurological or other medical conditions Bigliani Bigliani et aletal, 2000; Stephenson et aletal,, antipsychotics for therapeutic action. and substance misuse. Anticholinergic 2000). This hypothesisrequires substantia- drugs or benzodiazepines that do not inter- Higher in vivo binding to the D22 receptorsreceptors tion with the more sensitive and quantita- fere with DDferewith 22 dopamine receptors Burt et aletal,, inthe cortex thaninthe basalganglia is tive positron emissiontomography PET) 1976; Boyson et aletal, 1988) were not with- suggested as anindicator of favourable technique. However, in the extrastriatal drawn. The patient groups were compared profile for a putative antipsychotic structures such as thalamus, limbic and with a group of six normal control men temporal cortices, the D dopamine recep- compound. 22 mean ageˆ24 years, s.d.ˆ4) who underwent tor density is 5- to 25-fold lower than in a medical examination and a psychiatric Declaration of interest The the striatal structures, where they exist in interview in order to rule out any medical nanomolar concentrations Kessler et aletal,, condition. The Henri Mondor ethics com- Fondation pour la Recherche MeMedicale¨ dicale 7676 1993). The development of [[ Br]-FLB457, mittee approved the protocol. After a com- and the Fondation Lilly France supported a bromine-labelled benzamide radioligandradioligand pletepletedescriptiondescription of the study to the subjects,jects,sub X.X. in partduringpart during the study. for PET with picomolar affinity and a high written informed consent was obtained. selectivity for D22 and DandD33 recepreceptors dis-dis-tors sociation constant Ki D †ˆ0.018 nM)nM)0.018 Loc'h 2 Brain imaging *Presented in part atattheVIIth the VIIth International Congress et aletal, 1996), has made possible the compar- on Schizophrenia Research, Santa Fe,New Mexico,USA, ison of the binding of various antipsychotic Brain imaging, image analysis and deter-

17^21April1999. compounds to extrastriatal and striatal mination of the D22 dopamine blockade by

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TaTable b l e 1 Characteristics of the patients

Subject Age GenderPositive Negative DrugOral drug dose Plasma drugdrugPlasma Binding index )%) code )years))years) symptomsymptom symptomsymptom )mg/day) concentration score11 scorescore11 ))mmg/l)g/l) StriatumThalamus Temporal cortex

H1H1 3434 FF 16 29 Haloperidol 33 66 66.666.6 91.291.2 88.388.3 H2 2222 MM 14 19 Haloperidol 88 8.3 80.6 94.9 91.891.8 H3 4242 MM 2323 24 Haloperidol 15 2222 84.784.7 96.396.3 8989 H4 2929 FF 15 2121 Haloperidol 6060 5252 94.3 94.3 97.597.5

R1 41 MM 21 15 RisperidoneRisperidone 66 4141 67 92.2 92.2 R2R2 32 MM 17 25 RisperidoneRisperidone 88 4343 57 86.1 94.6 R3R3 3030 MM 2323 2222 RisperidoneRisperidone 12 5959 65.8 91.291.2 88.1

C1 4040 MM 2424 2828 Clozapine 200200 114 34.8 58.358.3 71.771.7 C2 32 MM 2020 23 Clozapine 400400 262262 17.817.8 51.851.8 71.671.6 C3 3737 FF 10 13 Clozapine 200200 434 45.945.9 7979 90.1

A1 MM 77 3232 Amisulpride 200200 153.88153.88 43.643.6 73.6 93.593.5 A2 2929 MM 19 2020 Amisulpride 400400 91.1 16.1 50.750.7 5353 A3 2323 MM 18 2222 Amisulpride 600 298.6 43.643.6 82.6 82.582.5 A4 21 MM 19 25 Amisulpride 1200 342.7 43.443.4 89.889.8 87.5 A5 2626 MM 12 24 Amisulpride 1000 390.8390.8 61.5 69.969.9 87.8

O1 3838 MM 17 35 Olanzapine 55 NDND 48.5 58.558.5 9090 O2 4040 MM 2424 2828 Olanzapine 1010 NDND 18.718.7 4343 83.783.7 O3 21 MM 17 30 Olanzapine 1010 NDND 43.743.7 64.364.3 68.768.7 O4 2525 MM 16 23 Olanzapine 2020 NDND 69.6 91.9 91.891.8

ND, not determined. 1. Positive and Negative Syndrome Scale )PANSS): each score represents the sum of seven items; a score of 7 means an absence of symptoms; the maximum score is 49.

the computation of a binding index were two 15-min images. Then the subjects were and putamen weredefined on five slices, performed according to a methodology removed from the tomograph for 60 min thalamus on four slices and temporal cor- described previously Xiberas et aletal, 2001).,2001). and afterwards placed in the same position tices on four slices below the lowest striatum Briefly, for each subject a 1.5 T Signa using a thermoplastic-modelled mask as well slice; finally, ROIs were defined in the cere- Imager General Electric, Milwaukee, WI) as skin marks withrespect to a laser beam bellar grey matter on four slices. provided 128 anatomical slices parallel to system, in order to acquire a late image series: Regional radioactivity concentrations the orbito-meatal line. Afterwards, 63 one 30-min and one 15-min image. Finally, a for each region injected dose- and decay- cerebralcerebralslicesslices parallel to the orbito-meatal second transmission scan was performed for corrected) were computed by pooling the linelinewerewere acquired with a Siemens HR+ co-registration purposes. corresponding ROI values and by summing positron tomograph of spatial resolution the left and right regional values. 2.5 mm; Knoxville, TX). Just before inject- Image analysis ing the [[ingthe 7676Br]-FLB457, venous blood was For each subject, the first PET image series sampled for plasma concentration of the was co-registrated on the magnetic reso- Determination of D22 antipsychotic drug. Approximately 1 mCi nance image MRI) using the first trans- dopamine receptor blockade: of [of[7676Br]-FLB457 was injected into each sub- mission scan Mangin et aletal, 1994).,1994). binding index computation ject mean s.d.)ˆ0.98 0.20) mCi for Because the radioactivity concentrated Regional radioactivity was measured for healthy subjects and 1.03 0.23) mCi for mainly in the striatum in the late image each sequential scan and plotted against patients, Mann±Whitney UUˆ53.5,53.5, PPˆ0.82),0.82), series, the corticalstructures could not be time. Specific binding in the ROIs was with a high specific activity of used for registration.Therefore, the second defined as the difference between radio- 264264++164164 mmCi/nmol for healthy subjects transmission scan was used for PET to activities in the ROIs and the cerebellum.

and 481481and ++299299 mmCi/nmol for patients MRI co-registration. Regions of interest The activity measured AAmm) in the ROIs Mann±Whitney UUˆ29,29, PPˆ0.08). After- ROIs) were drawn onthe co-registrated represents the sum of the free and non- wards, a first image series was acquired: MRI slices, following thevisible borders of specific binding) and bound radioligand two 5-min images, two 10-min images and the structures in each hemisphere. Caudate concentrations:

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AAmm ROIs)ˆAAsbsb ROIs)+CC Amisulpride Striatal and thalamic After extraction from alkalinised plasma by a binding indices wherewhere AA is the specifically bound radio- sbsb mixture of diethyl ether and chloroform, the Striatal and thalamic binding indices clearly active concentration in the ROIs and CC isis amisulpride was purified from a mmBondapakBondapak distinguished haloperidol-treated from the activity measured in the cerebellum, C18 column 5 mmm, 150m,150664.6 mm) using a atypical antipsychotic-treated patients: which represents under the assumption 90/10 mixture of phosphate buffer pH 3) indices were lower with atypical anti- that the concentration of D dopaminedopamine 22 and acetonitrile as mobile phase. Detection psychotics. Inthe thalamus, the D bindingbinding receptors in the cerebellum is negligible 22 was performed using a fluorimetric detector indices inducedby clozapine, amisulpride with respect to the concentration in the set atsetat ll ˆ280 nm and ll ˆ370 nm. The and olanzapinewere lower than that other regions) both free ligand and non- exex emem detection limit was 0.5 mmg/l.g/l. induced by haloperidol.Analogous trends specific binding. This method has been were detected in the thalamus and striatum validatedvalidated in vitroinvitro Altar et aletal, 1985) and of risperidone-treated patients. in vivoinvivo using PET with previous D22 dopa-dopa- mine receptor ligands Farde et aletal, 1985),,1985), Olanzapine 7676 as well as for the [ Br]-FLB457 Xiberas Owing to technical reasons, plasma drug Temporal binding indices et aletal, 2001). Hence, for each patient a concentration determinations were not Binding indices in the temporal cortex were binding index BI) of the antipsychotic available.available. compound was derived from the patient's similarly high, whatever the antipsychotic measured regional radioactivity concen- compound.compound. trations in the striatum, the extrastriatal RESULTSRESULTS regions thalamus, temporal cortex) and the DISCUSSION cerebellum at the time of 165 min, taking Individual characteristics of patients and the measures of control subjects as a baseline: treatments, as well as antipsychotic plasma Patients treated with the usual antipsychotic concentrations and binding index values, dose ranges of haloperidol, risperidone, regional Am ÀC† BI %†ˆ100À100 patients are reported in Table 1. Figure 1 shows an clozapine, amisulpride and olanzapine had regional Am ÀC†controls example of time±radioactivity curves. Paired a similarly high D22 dopamine receptor block- comparisons for the binding indices in ade in the temporal cortex, as estimated striatal and extrastriatal regions across by the binding index of [7676Br]-FLB457. Plasma drug concentration treatment groups Table 2) showed that In contrast, the atypical antipsychotic the striatal and thalamic binding indices drugs induced a significantly lower D determination 22 graded the haloperidol and atypical anti- binding index than haloperidol in basal Haloperidol psychotics Fig. 2). This was not the case gangliaganglia i.e. in the thalamus and particularly After extraction from alkalinised plasma in the temporal cortex. in theinthe striatum).striatum). by a mixture of hexane/isoamylic alcohol, haloperidol was purified from a Kromasil C8 column 5 mmm, 250m,250664.6 mm) using a 73/23 mixture of phosphate buffer pH 3) and acetonitrile as mobile phase. The wave- length was set at 280 nm. The detection limit was 1.0 mmg/l.g/l.

RisperidoneRisperidone After extraction from alkalinised plasma by a mixture of hexane/ethylacetate, the risperidone was purified from a Kromasil C8 column with the same characteristics as those described for haloperidol.

ClozapineClozapine After extraction from alkalinised plasma by a mixture of hexane/isoamylic alcohol, the clozapine was purified from a Spherisorp C8 column 5 mmm, 250m,250664.6 mm) using a 55/55/40/5mixture40/5 mixture of phosphate buffer pH 3), acetonitrile and methanol as mobile phase. The wavelength was set at 230 nm. Fig.1Fig.1 Time^radioactivity curves in the striatum of control subject group and of patients treated with various The detection limit was 2.5 mmg/l.g/l. dosages of haloperidol.

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TaTable b l e 2 Comparison of binding indices in striatum, thalamus and temporal cortex

Intergroup comparisons Paired-group comparisons )mean )s.d.)) by Mann^Whitney test by Kruskal^Wallis test Haloperidol v. risperidone HaloperidolHaloperidol v. clozapineclozapine HaloperidolHaloperidol v. amisulpride HaloperidolHaloperidol v. olanzapineolanzapine

Striatum HHˆ11.8;11.8; PPˆ0.020.02 81.5 )11.5) v. 63.3 )5.5))5.5)63.3 81.5 )11.5) v.v. 32.8 )14.2))14.2)32.8 81.5 )11.5) v. 41.6 )16.3) 81.5 )11.5) v.v. 45.1 )20.9))20.9)45.1 UUˆ1.0; PPˆ0.11 UUˆ0.0; PPˆ0.050.05 UUˆ0.0; PPˆ0.01 UUˆ1;1; PPˆ0.05 ThalamusThalamus HHˆ11.3; PPˆ0.02 94.2 )2.1))2.1)94.2 v.v. 89.8 )3.3))3.3)89.8 94.2 )2.1))2.1)94.2 v.v. 63.0 )14.2) 94.2 )2.1) v. 73.3 )14.8) 94.2 )2.1))2.1)94.2 v. 64.4 )20.4))20.4)64.4 UUˆ1.5; PPˆ0.11 UUˆ0.0; PPˆ0.050.05 UUˆ0.0; PPˆ0.020.02 UUˆ1;1; PPˆ0.05 Temporal cortex HHˆ5.7;5.7; PPˆ0.23 91.7 )4.2))4.2)91.7 v. 91.6 )3.3))3.3)91.6 91.7 )4.2))4.2)91.7 v.v. 77.8 )10.7) 91.7 )4.2))4.2)91.7 v.v. 80.9 )16.1))16.1)80.9 91.7 )4.2))4.2)91.7 v. 83.6 )10.5) UUˆ6.0; PPˆ11 UUˆ2.0;2.0; PPˆ0.23 UUˆ3.0; PPˆ0.11 UUˆ4.5; PPˆ0.340.34

patient's measured regional radioactivity antipsychotic treatments. Indeed, by using concentrations in the striatum, the extra- thethemeanmean cerebellar value observed in the striatal regions thalamus, temporal cortex) healthyhealthysubjects as a reference, under- and the cerebellum 165 min after injection estimation of binding index values was Fig. 1), using the measures in control sub- below 5% in the striatum but ranged from jects as a baseline. The time was chosen 4% haloperidol) to 12% clozapine) in the from modelling studies in primates, because temporal cortex. it tallies with the duration required for the This underestimation, more marked in radioligand's equilibrium in the extra- cortical than in striatal structures, strength- striatal regions Delforge et aletal, 1999).,1999). ens the observation of a high binding index However, according to the same model, in cortical regions with all antipsychotics equilibrium is reached only at ttˆ300 min300min and the differential binding index values after injectionin striatal regions. In one con- between haloperidol and atypical compounds trol subject, we measured the concentration in the basal ganglia. This observation is in of the radioactivity in the striata at 165 and keeping with a modelling study, correlating

315 min afterinjection: an increase of 10% the affinity of a ligand with the BBmaxmax in theinthe only 139139only v.v. 152 nCi/ml) was observed at structure studied. According to that model- 315 min. Thus, the binding in the striatum ling, the apparent affinity of a radioligand

is probably slightly underestimated and is correlated with the BBmaxmax in the structure:

values reported for striatal regions should when thewhenthe BBmaxmax is low, the apparent affinity

not be considered as effective D22 receptorreceptor of the radioligand to its receptor increases occupancy figures but as approximate Delforge et aletal, 1999).,1999). values. They are, nevertheless, useful to

compare the striatal D22 receptor blockade inducedinduced in vivoinvivo by various antipsychotic Consistency with previous ex vivoexvivo drugs.drugs. findings in animals

The high D22 blockade induced in the tem- poral cortex by each of the five antipsychotic Picomolar affinity radioligand drugs is consistent with reports using dif- The picomolar affinity of [7676Br]-FLB457 for ferent methodologies. The topographical

DD22 receptors accounts for the detection of a selectivity of atypical antipsychotics on decrease of cerebellar radioactivity values dopamine blockade has been reported in treated patients, which is likely to reflect previously from ex vivoexvivo measurements in some degree of occupancy of the small con- animals. For instance, studies have demon-

centration of cerebellar D22 receptors. This strated a higher affinity of amisulpride for Fig. 22Fig. Binding indices of haloperidol, risperidone, was not detected in previous studies using DD22 dopamine receptors in the temporal lower-affinity D radioligands. Although regions than in striatum Schoemaker et aletal,, clozapine, amisulpride and olanzapine in the striatum 22 the cerebellar radioactivity cannot be consid- 1997). Also, chronic treatment with cloza- )a), thalamus )b) and temporal cortex )c). erederedas solely reflecting non-specific binding pine has been shown specifically to up- 7676 of the [[ofthe Br]-FLB457, in the conditions of regulate cortical D22 mRNA turnover and the present study the use of a subtractive cortical DcorticalD receptor binding, at variance Methodological considerations 22 operaoperatortor in the binding index computation with haloperidol, which seems to upregu- Long-time-frame PET imaging i.e. regional AAmm77CC) limits the incidence late both striatal and cortical D22 receptorsreceptors For each patient, a binding index of the of theofthecerebellar specific binding for com- Lidow & Goldman-Rakic, 1994). Atypical antipsychotic drug was derived from the parison of the binding index under various antipsychotics raise dopamine turnover

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more in limbic structures than in striatum, whereas traditional antipsychotics affect CLINICAL IMPLICATIONS the dopamine turnover in both regions to

the same degree Westerink et aletal, 1977). InIn,1977). && Cortical D22 dopamine receptors are a common target of both traditional and addition, the cc-fos-like immunoreactivity is atypical antipsychotics for therapeutic action. increased by atypical antipsychotics in lim- bic areas and in cortices, whereas traditional && In the basal ganglia, atypical antipsychotics antagonise the dopamine transmission antipsychotics also lead to an increased cc-- mediated by the D22 receptor to a lower level than traditional antipsychotics. fos expression in the dorsolateral striatum && The co-occurrence of a highin vivo binding to the D receptors in the cortex and a Fink-Jensen & Kristensen, 1994). 22 lower binding in the basal ganglia could be an indicator of a favourable benefit/risk profile for a putative antipsychotic compound. Consistency with previous invivo findings in humans LIMITATIONS Our results obtained with a quantitative && Owing to the small patient samples, inter-individual variability was not assessed imaging technique are in agreement withwith extensively. previousprevious in vivoinvivo reports using a radioligand with the same picomolar affinity for D re-re- && 22 The binding indices approximate the effective D22 receptor occupancy. ceptors [ceptors[123123I]-epidepride) and single photon emission tomography to assess the && The study was not designed to assess therapeutic effects longitudinally.

`occupancy' of D22 receptors by antipsychotic drugs in the striatum and temporal cortex. Indeed, the elevated occupancy figures observed with traditional compounds halo- peridol, fluphenazine, flupenthixol, pipotia- XAVIER XIBERAS, MD,JEAN LUC MARTINOT,MD,INSERM U 334, Service Hospitalier FreFrederic¨ de¨ ric Joliot; LUC zine, droperidol) in both temporal mean MALLET, MD, A. Chenevier Ho^pital,Crepital,Creteil,¨ teil, and INSERM U 334, Service Hospitalier FreFrederic¨ de¨ ric Joliot,Orsay; © 82%) and striatal mean 73%) regions ERIC ARTIGES, MD,C. LOC'H, BSc, B. MAZIEMAZIERE,RE, PharmD,PharmD,INSERM INSERM U 334, Service Hospitalier FreFrederic¨ de¨ ric Joliot, Orsay; MARIE LAURE PAILLEPAILLERE-MARTINOT© RE-MARTINOT MD,PitieMD, Pitie-Salpetriere¨ -Salpeª trie© re HoHopital,ª pital, Paris, France Bigliani Bigliani et aletal, 1999), and the small differ- ence between striatal and temporal cortex CorrespCorrespondence:Jean-Lucondence:Jean-Luc Martinot,INSERUM U 334, SHFJ,CEA, 4 Place Gl.Leclerc,Gl.Leclerc,91401Orsay, 91401Orsay, blockade were analogous to those deter- France. E-mail: martinot@@shfj.cea.frshfj.cea.fr mined in the haloperidol-treated patients of the present study. Thus, although a relative First received 13 February 2001, final revision 29 June 2001, accepted 6 July 2001)

temporal cortex selectivity in D22 blockadeblockade Pilowsky Pilowsky et aletal, 1997; Bigliani et aletal, 2000),2000) appears to characterise atypical anti- ACKNOWLEDGEMENTS and sertindole in vivoinvivo:a[:a[12123 3I]epidepride single photon psychotics, a similar high D22 blockade in emission tomography SPET) study. Psychopharmacology,, 150150,132^140. both temporal and striatal regions is This study was possible through a BIOMED 2 grant induced by usual antipsychotic doses of of the European Union, coordinated by Professor Boyson, S. J., McGonicle, P., Luthin, G. R., et aletal "19 8 8) traditional antipsychotics. Lars Farde. Dr Evelyne Chanut Biology Laboratory, Effects of chronic administration of antipsychotic and anticholinergic agents on densities of D dopamine and Paul Guiraud Hospital, Villejuif ) is acknowledged 22 On the whole, the convergence of muscarinic cholinergic receptors in rat striatum. JournalJournal forhaloperidol, risperidone and clozapine plasma ex vivoexvivo andand in vivoinvivo data strongly suggests of Pharmacology and Experimental Therapeutics,, 244,, concentration determinations and Muriel Canal that cortical D dopamine receptors are a 987^993. 22 Sanofi-Synthelabo)Sanofi-Synthe¨ labo) is acknowledged for amisulpride common target of both traditional and plasma concentration determinations. Burt, D. R., Creese, I. & Snyder, S. H."19 "1976) 76) BindingBinding atypical antipsychotics for therapeutic interaction of lysergic acid diethylamide and related agents with dopamine receptors in the brain. Molecular action.action. Pharmacology,, 1212, 631^638. Finally, from a clinical point of view, REFERENCES Chivers, J. K., Gommeren,W., Leysen, et aletal "19 8 8) our results are in keeping with the asso- Comparison of the in vitroinvitro receptor selectivity of ciation of antipsychotic efficacy attributed Altar,Altar,C.A.,O'Neils,S.,Walter,R.J.Jr., C. A.,O'Neils, S.,Walter, R. J. Jr., et aletal "19 8 5) substituted benzamine drugs for the brain to an action on meso-cortico-limbic Brain dopamine and serotonin receptor sites revealed neurotransmitter receptors. Journal of Pharmacy by digital subtraction autoradiography. Science,, 228,, and Pharmacology,, 4040,415^421., 415^421. dopamine pathways) and lower extra- 597^600. pyramidal side-effects attributed to an Coukell, A. J., Spencer,C. M. & Benfield, P."19 "1996) 9 6) American Psychiatric Association"1994) Diagnostic Amisulpride. A review of its pharmacodynamic antidopaminergic activity in the dorso- and Statistical Manual of Mental Disorders 4th edn) and pharmacokinetic properties and therapeutic lateral striatum) with atypical antipsy- DSM^IV).Washington,DSM ^ IV).Washington, DC: APA. efficacy in the management of schizophrenia. CNS Drugs,, 66, 237^256. chotics than with traditional compounds. Bigliani,V., Mulligan, R. S., Acton, P. D., et aletal "1999)"1999) Searching for a high in vivoinvivo binding to the In vivoInvivo occupancy of striatal and temporal cortical Delforge, J., Bottlaender, M., Loc'h, C., et aletal "1999)"1999) DD /D/D dopamine receptors by typical antipsychotic Quantification of extrastriatal D receptors using a very DD receptors in the cortex co-occurring 22 33 22 22 drugs. [123123I]-epidepride single photon emission high affinity ligand FLB 457) and the multi-injection with a lower binding in the basal ganglia tomography SPET) study. British Journal of Psychiatry,, approach. Journal of Cerebral Blood Flow and Metabolism,, therefore could be suggested as an indicator 175, 231^238. 1919,533^546. of a favourable benefit/risk profile for a __ ,, __ ,, __ ,, et aletal "2000)"2000) Striatal and temporal Editions du Vidal"19 "1993) 93) Dictionnaire Vidal.Paris:

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