Does fast dissociation from the dopamine D-2 receptor explain the action of atypical antipsychotics?: A new hypothesis

Objective: Although atypical antipsychotics are becoming the treatment of c hoice for schizophrenia, what makes an antipsychotic "atypical" is not clea r. 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-HT2 and dopamine D-4 receptors in atypicality. Results: Neuroimaging data show that optimal dopamine D-2 occupancy is suff icient to produce the atypical antipsychotic effect. Freedom from motor sid e effects results from low D-2 occupancy, not from high 5-HT2 occupancy. If D-2 occupancy is excessive, atypicality is lost even in the presence of hi gh 5-HT2 occupancy Animal data show that a rapid dissociation from the D-2 receptor at a molecular level produces the atypical antipsychotic effect. I n vitro data show that the single most powerful predictor of atypicality fo r the current generation of atypical antipsychotics is fast dissociation fr om the D-2 receptor, not its high affinity at 5-HT2, D-4, or another recept or Conclusions: The authors propose that fast dissociation from the D-2 recept or makes an antipsychotic more accommodating of physiological dopamine tran smission, permitting an antipsychotic effect without motor side effects, pr olactin elevation, or secondary negative symptoms. in contrast to the multi receptor hypotheses, the authors predict that the atypical antipsychotic ef fect can be produced by appropriate modulation of the D-2 receptor alone; t he blockade of other receptors is neither necessary nor sufficient.