What are the optimal pharmacokinetic properties of antipsychotic medications?

Sensitization of the dopaminergic system has been proposed as a pathogenic mechanism of psychosis. It has been reported in sensitized animals that the proportion of high-affinity dopamine 2 (D2) receptors is increased, without changes in the total amount of D2 receptors. This increase induces an exaggerated postsynaptic transmission of the dopamine signal, which is attenuated by antipsychotic D2 antagonists. In this report, I simulated D2 receptor binding of dopamine and antipsychotics under pathologic state, and investigated pharmacological conditions that would return the increased dopamine binding back to normal levels in both resting and burst dopamine concentrations. I found that D2 antagonists with small Koff values at a concentration 2.5 times the Ki closely mimicked normal dopamine binding. Under these conditions, the apparent receptor occupancy of the drug was calculated as 70%.