Implications of brain imaging for the management of schizophrenia.
Positron emission tomography (PET) can be used to explore relationships between central neuroreceptor occupancy, psychotropic drug blood levels and clinical effects. Treatment with conventional neuroleptics induces high (70-90%) dopamine (D2)-receptor occupancy. The risk of extrapyramidal side effects increases at D2-receptor occupancies above 80%. Standard doses of clozapine induced a low (20-67%) D2-receptor occupancy, but very high (85-90%) 5-hydroxytryptamine (5-HT2A)-receptor occupancy. The novel antipsychotics risperidone and olanzapine induced high occupancy of both D2 and 5-HT2A receptors at suggested standard doses. The occurrence of extrapyramidal side effects in some patients in the higher dose ranges does not support the view that 5-HT2A-receptor occupancy completely prevents the development of extrapyramidal side effects. These results emphasize the need for further exploration of the low dose ranges of risperidone and olanzapine. A preliminary analysis of an ongoing PET study showed that a schizophrenic patient treated with sertindole at 20 mg/day had a D2-receptor occupancy of below 70%. Further studies are needed to show whether sertindole is the first new antipsychotic that induces low occupancy in the clinical dose range, suggesting a mechanism of action distinct from that of classical neuroleptics and analogous to that of clozapine.
Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
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Nyberg
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Nilsson
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Okubo
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Halldin
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Farde
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D001931:Brain Mapping; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012307:Risk Factors; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy*; D014055:Tomography, Emission-Computed
D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C066304:sertindole