Regional selectivity of novel antipsychotics

M. Kopecek, C. Höschl and T. Hájek

Psychiatric Centre Prague, Ústavní 91, 181 03 Praha 8—Bohnice, Czech Republic

Xiberas et al (2001) measured D2 receptor occupancy in striatum, thalamus and temporal cortex in patients treated with haloperidol, risperidone, amisulpride, clozapine and olanzapine. On the basis of their findings, they conclude that in the striatum and in the thalamus atypical antipsychotics induce a significantly lower D2 binding index than haloperidol does. Their results are consistent with previous studies showing only small differences between striatal and temporal cortex blockade by traditional compounds and relatively selective D2 blockade in temporal cortex caused by atypical antipsychotics (Pilowsky et al, 1997; Bigliani et al, 2000).

Looking at the data from Xiberas et al (2001), we came to different conclusions. Using equipotent doses of antipsychotics (doses which lead to the same occupation of D2 receptors in the striatum), no differences in thalamo-striatal and temporostriatal indices between typical and atypical antipsychotics could be shown (Table 1). We suggest that atypical antipsychotics do not exert special temporal lobe or limbic selectivity. The selectivity depends more on the dose than on the type of antipsychotic (typical v. atypical). This is in agreement with Nyberg & Farde (2000) and Geddes et al (2000), who argue that non-equipotent doses can partly explain differences between classical and novel antipsychotics.


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Table 1 D2 dopamine receptor binding indices in striatum, thalamus and temporal cortex, and the ratios of temporal/striatal (temporo-striatal) and thalamic/striatal (thalamo-striatal) binding indices in patients taking traditional and atypical antipsychotics (data from Xiberas et al, 2001)
 

EDITED BY KHALIDA ISMAIL

REFERENCES

Bigliani, V., Mulligan, R. S., Acton, P. D., et al (2000) Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [1231]epidepride single photon emission tomography (SPET) study. Psychopharmacology, 150, 132-140.[CrossRef][Medline]

Geddes, J., Freemantle, N., Harrison, P., et al (2000) Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ, 321, 1371-1376.[Abstract/Free Full Text]

Nyberg, S. & Farde, L. (2000) Non-equipotent doses partly explain differences among antipsychotics — implications of PET studies. Psychopharmacology, 148, 22-23.[CrossRef][Medline]

Pilowsky, L. S., Mulligan, R. S., Acton, P. D., et al (1997) Limbic selectivity of clozapine. Lancet, 350, 490-491.[CrossRef][Medline]

Xiberas, X., Martinot, J. L., Mallet, L., et al (2001) Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. British Journal of Psychiatry, 179, 503-508.[Abstract/Free Full Text]


 

Authors' reply

J. L. Martinot, X. Xiberas, E. Artiges, C. Loc'h, B. Mazière and M. L. Paillère

INSERM U334 and Commissariat à l'Energie Atomique, Service Hospitalier Frédéric Joliot, 4 Place Gl. Leclerc, 91401 Orsay, France

EDITED BY KHALIDA ISMAIL

Declaration of interest

Our team is funded by a donation from the INSERM. Also X.X. was partly funded by grants from the Fondation pour la Recherche Médicale and the Commissariat à l'Energie Atomique.

We thank Dr Kopecek et al for their interest in our paper (Xiberas et al, 2001b). They conclude that atypical antipsychotics do not exert special temporal or limbic selectivity, which depends instead on drug dosages. First, we believe that generalisations drawn from data obtained from five patients, each one treated with a different antipsychotic drug, are not sound, because of intersubject variability. For instance, should Dr Kopecek et al have considered plasma drug concentrations and patient H2 of our article, their conclusion would have been modified. In our article, we drew conclusions from the statistical comparisons of [76Br]-FLB457 measures obtained with positron emission tomography (PET) in subgroups of patients, receiving the usual dosage recommended by the pharmaceutical firms for each antipsychotic drug, for treating psychotic episodes.

Second, we have already reported the importance of dosage when interpreting neuroimaging measures of regional D2 dopamine receptor blockade by antipsychotic drugs (Xiberas et al, 2001a). Inspection of the table that Kopecek et al draw from our article suggests that for a striatal D2 receptor binding index approaching 65-70%, the atypical antipsychotics induce extrastriatal/striatal indices comparable with that induced by the lowest oral dosage of haloperidol reported. This is consistent with our previous publication (Xiberas et al, 2001a) where we specifically highlighted the dose-dependence of extrastriatal/striatal D2 blockade, from a study in a larger sample of patients treated with an atypical antipsychotic. We demonstrated that plasma concentrations were more accurately related than daily oral doses to the different regional binding profiles determined with PET. Clearly, two binding profiles could be distinguished depending on the plasma concentration of the drug: low striatal binding associated with marked extrastriatal binding for low plasma concentrations, or marked binding in both striatal and extrastriatal regions for higher plasma concentrations. This may be applicable to both atypical and typical compounds, if very low doses of typical neuroleptics (i.e. below the recommended therapeutic dose range) are considered, but this is a speculation. Therefore, having previously highlighted the effect of dosage (Xiberas et al, 2001a), we chose to highlight in our second article (Xiberas et al, 2001b) that, at plasma concentrations obtained in actual clinical practice, and compared with haloperidol, various atypical antipsychotic drugs have a regional binding profile that is higher in mesocorticolimbic regions than in striatum.

REFERENCES

Xiberas, X., Martinot, J. L., Mallet L., et al (2001a) In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia. Journal of Clinical Psychopharmacology, 21, 207-214.[CrossRef][Medline]

Xiberas, X., Martinot, J. L., Mallet L., et al (2001b) Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. British Journal of Psychiatry, 179, 503-508.[Abstract/Free Full Text]





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