Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis

Am J Psychiatry. 2001 Mar;158(3):360-9. doi: 10.1176/appi.ajp.158.3.360.


Objective: Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics.

Method: Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT(2) and dopamine D(4) receptors in atypicality.

Results: Neuroimaging data show that optimal dopamine D(2) occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D(2) occupancy, not from high 5-HT(2) occupancy. If D(2) occupancy is excessive, atypicality is lost even in the presence of high 5-HT(2) occupancy. Animal data show that a rapid dissociation from the D(2) receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that the single most powerful predictor of atypicality for the current generation of atypical antipsychotics is fast dissociation from the D(2) receptor, not its high affinity at 5-HT(2), D(4), or another receptor.

Conclusions: The authors propose that fast dissociation from the D(2) receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. In contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.

Publication types

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

MeSH terms

  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Benzodiazepines
  • Brain / drug effects
  • Brain / metabolism
  • Clozapine / pharmacokinetics
  • Clozapine / pharmacology
  • Clozapine / therapeutic use
  • Dopamine D2 Receptor Antagonists*
  • Haloperidol / pharmacokinetics
  • Haloperidol / pharmacology
  • Haloperidol / therapeutic use
  • Humans
  • Olanzapine
  • Pirenzepine / analogs & derivatives*
  • Pirenzepine / pharmacokinetics
  • Pirenzepine / pharmacology
  • Pirenzepine / therapeutic use
  • Psychotic Disorders / diagnostic imaging
  • Psychotic Disorders / drug therapy*
  • Psychotic Disorders / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D4
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism
  • Risperidone / pharmacokinetics
  • Risperidone / pharmacology
  • Risperidone / therapeutic use
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism
  • Terminology as Topic
  • Tomography, Emission-Computed / statistics & numerical data


  • Antipsychotic Agents
  • DRD4 protein, human
  • Dopamine D2 Receptor Antagonists
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Benzodiazepines
  • Receptors, Dopamine D4
  • Pirenzepine
  • Clozapine
  • Haloperidol
  • Risperidone
  • Olanzapine