Imaging psychotropic drug action

Of direct clinical relevance are imaging studies of antipsychotic drug action where clinical efficacy and side-effects are related to receptor occupancy. (9,28>

Many studies have investigated the occupancy of striatal dopamine D1 and D2 and cortical serotonin 5-HT2 receptors by neuroleptic drugs. Farde's group first demonstrated that clinically efficacious doses of a variety of classical antipsychotics cause between 65 per cent and 89 per cent occupancy of central dopamine D 2

receptors/.9,28ยป Higher receptor occupancy ({gt}85 per cent) is associated with an increased incidence of extrapyramidal side effects. Thus, there may be a therapeutic window for occupancy of between 65 per cent and 85 per cent, which is antipsychotic and yet less likely to cause extrapyramidal side effects. In contrast, treatment with classical antipsychotics produces variable levels of occupancy of striatal D 1 receptors. Interestingly, efficacious doses of the atypical antipsychotic clozapine are associated with a relatively low D2 receptor occupancy (38-63 per cent) and a D1 occupancy of 38 to 52 per cent.(928) This unexpected finding of low D2 receptor occupancy, reproduced in different patient groups with both PET and SPET techniques, has challenged theories of a simple relationship between D 2 occupancy per se and clinical efficacy. Further evidence for this view comes from studies showing that schizophrenic antipsychotic non-responders have the same levels of dopamine D2 occupancy as responders and that occupancy occurs as rapidly as 2 h after acute administration of the antipsychotic yet efficacy takes weeks to appear.

PET/SPET is also proving useful in the characterization of atypical antipsychotics. The binding of antipsychotic drugs to central 5-HT 2 receptors is a possible candidate for the mechanism of 'atypicality' and studies suggest high cortical 5-HT 2 occupancy with risperidone (80 per cent) and clozapine (84-90 per cent). (9,28,29> Conclusions

So far, the PET and SPET radiotracer techniques and applications described have not yielded a diagnostic test, or an exact guide to outcome in the major psychiatric illnesses. However, they have been immediately valuable in assessing the receptor occupancy effects of antipsychotic drugs and of mapping the neural correlates of dysfunctional cognitive processes and psychiatric symptoms. The definition of an endophenotype of a major psychiatric illness is perhaps some way off but in the long term the techniques will almost certainly provide essential information about the pathophysiology of psychiatric illnesses.

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