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

Mol Psychiatry. 1998 Mar;3(2):135-40. doi: 10.1038/sj.mp.4000327.

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 (i.e. > 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', resperidone 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antipsychotic Agents / classification
  • Antipsychotic Agents / pharmacokinetics*
  • Antipsychotic Agents / therapeutic use
  • Binding, Competitive
  • Clozapine / pharmacokinetics
  • Clozapine / therapeutic use
  • Dopamine / physiology*
  • Dopamine Antagonists / pharmacokinetics*
  • Dopamine Antagonists / therapeutic use
  • Dopamine D2 Receptor Antagonists
  • Humans
  • Models, Psychological
  • Protein Binding
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Serotonin / metabolism*
  • Risperidone / pharmacokinetics
  • Risperidone / therapeutic use
  • Schizophrenia / diagnostic imaging
  • Schizophrenia / drug therapy*
  • Serotonin / physiology*
  • Serotonin Antagonists / pharmacokinetics*
  • Serotonin Antagonists / therapeutic use
  • Tomography, Emission-Computed*

Substances

  • Antipsychotic Agents
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin
  • Clozapine
  • Risperidone
  • Dopamine