Are animal studies of antipsychotics appropriately dosed?: Lessons from the bedside to the bench

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D-2 receptors, and most are effective at doses that lead to 60% to 80% D-2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this "bedside" information to inform the "bench," we measured D-2 occupancy in rats using a method similar in principle to the [C-11]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D-2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D-2 occupancy is > 80%, 2) very low noses, 0.06 mg/kg/sc, cause acute D-2 occupancy of 75%; 3) and even doses that acutely saturate D-2 receptors give little D-2 occupancy after 24 hours clue to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D-2 occupancy and inappropriately low D-2 occupancy between doses. We exemplify how this closing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench-using D-2 occupancy as a mediating variable-will lead to more valid animal models.