D2 occupancy, extrapyramidal side effects and antipsychotic drug treatment: a pilot study with sertindole in healthy subjects.
Acute extrapyramidal syndromes (EPS) are frequently recorded during treatment with classical neuroleptic drugs. In patients with EPS a consistent finding is high central D2-receptor occupancy (> 80%) as demonstrated with positron emission tomography (PET). The exception is clozapine, an atypical antipsychotic which has low EPS liability and also induces a low D2 occupancy (20-67%). We have proposed that the PET demonstration of low D2 occupancy at antipsychotic dose levels can be viewed as a strategy to confirm atypicality. There have been strong incentives in recent years to discover new drugs which do not induce EPS, but so far no drug has been shown unequivocally to have the low D2 occupancy and EPS liability reported for clozapine. Sertindole is a new antipsychotic drug which has shown a low incidence of acute EPS in clinical studies. In the present study PET was used to measure central D2-dopamine receptor binding in the basal ganglia at baseline and 6 h after oral administration of 4 mg sertindole to two healthy males. D2-dopamine receptor occupancy was 15% in one subject and 6% in the other. The low occupancy level demonstrated at 4 mg indicates the need for a PET study in patients at the suggested clinical dose level of 12-24 mg a day. In particular, it is important to determine whether sertindole induces antipsychotic effects at a D2 occupancy level which is lower that found in patients treated with classical antipsychotics.
Farde
L
L
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Mack
R J
RJ
Nyberg
S
S
Halldin
C
C
D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D001921:Brain / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D010865:Pilot Projects; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012457:Salicylamides / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; C066304:sertindole