A new framework for investigating antipsychotic action in humans: lessons from PET imaging

Abstract

With a decade of neuroreceptor imaging of antipsychotics behind us, this article attempts to synthesise what has been learnt about the mechanism of action of antipsychotics using these techniques. The data show that: (i) the ‘typical’ antipsychotics bind mainly to the dopamine D₂ receptor, and that 60–80% D₂ occupancy may provide optimal antipsychotic response with little extrapyramidal side effects; (ii) all the clinically available ‘atypical’ antipsychotics show a higher occupancy of the 5-HT₂ than D₂ receptors; (iii) however, these ‘atypical’ antipsychotics differ in their D₂ occupancy. The D₂ occupancy of risperidone is within the typical range (ie > 60%) while that of clozapine is clearly lower (<60%); (iv) antipsychotics with combined 5-ht₂/D₂ antagonism lose some of their ‘atypical’ properties if used in doses where their D₂ occupancy is too high (>80%). Based on these data a framework is suggested wherein antipsychotics may be classified on the basis of their D₂ and 5-HT₂ occupancy in patients at steady state while taking clinically relevant doses. Within this framework typical antipsychotics are classified as ‘high-D₂’, risperidone as ‘high-D₂ high-5HT₂’ and clozapine as a ‘low-D₂ high-5HT₂’ antipsychotic. The justification, limitations and the value of this framework in understanding and investigating newer antipsychotics is discussed.