Increased dopamine D₂ receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study

Abstract.

Rationale: Dopamine D₂ receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D₂ receptor upregulation has long been postulated as central to tardive dyskinesia (TD). Objective: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D₂ receptor up-regulation also occurs in humans. Methods: The long-term effects of traditional and novel antipsychotics on dopamine D₂ receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D₂ receptors were measured using ¹¹[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. Results: There was a significant increase in the D₂ BP in both groups combined that reached 34%. The increases in the D₂ BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D₂ receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D₂ receptors. Conclusion: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D₂ receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D₂ receptors are associated with a substantial increase in D₂ receptor binding. The present data in humans agree well with animal data that implicate D₂ receptor-mediated mechanisms in motor hyperactivity.