Does Fast Dissociation From the Dopamine D2 Receptor Explain the Action of Atypical Antipsychotics?: A New Hypothesis

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-HT2 and dopamine D4 receptors in atypicality. RESULTS: Neuroimaging data show that optimal dopamine D2 occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D2 occupancy, not from high 5-HT2 occupancy. If D2 occupancy is excessive, atypicality is lost even in the presence of high 5-HT2 occupancy. Animal data show that a rapid dissociation from the D2 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 D2 receptor, not its high affinity at 5-HT2, D4, or another receptor. CONCLUSIONS: The authors propose that fast dissociation from the D2 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 D2 receptor alone; the blockade of other receptors is neither necessary nor sufficient.