Central D2 receptor occupancy and effects of zuclopenthixol acetate in humans

Repeated positron emission tomography (PET) measurements of D2 receptor occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2 receptor occupancy was 51%, 71% and 75% after 7 h and 75%, 83% and 87% after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2 receptor occupancy exceeded the 70% assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50-150 mg ZPTA should induce very high D2 receptor occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2 receptor occupancy calls for careful assessment of acute extrapyramidal symptoms.