Breakthrough dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time

Antipsychotics often lose efficacy in patients despite chronic continuous treatment. Why this occurs is not known. It is known, however, that withdrawal from chronic antipsychotic treatment induces behavioral dopaminergic supersensitivity in animals. How this emerging supersensitivity might interact with ongoing treatment has never been assessed. Therefore, we asked whether dopamine supersensitivity could overcome the behavioral and neurochemical effects of antipsychotics while they are still in use. Using two models of antipsychotic-like effects in rats, we show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding. Treatment failure occurred despite high levels of dopamine D-2 receptor occupancy by the antipsychotic and was at least temporarily reversible by an additional increase in antipsychotic dose. To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system and observed that antipsychotic failure was accompanied by opposing changes across the synapse: tolerance to the ability of haloperidol to increase basal dopamine and dopamine turnover on one side, and 20 - 40% increases in D-2 receptor number and 100 - 160% increases in the proportion of D-2 receptors in the high-affinity state for dopamine (D-2 (High)) on the other. Thus, the loss of antipsychotic efficacy is linked to an increase in D-2 receptor number and sensitivity. These results are the first to demonstrate that breakthrough supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy. These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics.