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Antipsychotic drugs are first line treatment in schizophrenia.The dopamine D2 receptor system is a major target of antipsychotic drugs.The treatment with antipsychotics lead to multiple outcomes, including a diminuished long-term efficacy.Here putative mechanistic aspects of the antipsychotic treatment outcomes varibility are discussed.All antipsychotics bind to the dopamine D2 receptor. An “optimal” level of D2 receptor blockade with antipsychotics is thought to ameliorate the positive symptoms of schizophrenia. However, persistent D2 receptor blockade is associated with a deteriorating clinical response in a subset of patients. Interestingly, antipsychotics with a weaker D2 receptor binding profile appear somewhat superior in this respect. This evidence challenges the hypothesis that D2 receptor blockade is the sole mechanism of antipsychotic efficacy and points to consistent inter-individual responses to antipsychotic treatment.Here, we hypothesize that clinically effective doses of antipsychotics would lead to the formation of a D2 receptor “reserve” that is likely composed of presynaptic dopamine D2 autoreceptors. The majority of the remaining postsynaptic dopamine receptors are instead occupied by antipsychotics. Endogenous dopamine would then mainly interact with this D2 autoreceptor reserve, thereby reducing the presynaptic synthesis and release of dopamine and resulting in an indirect antipsychotic effect. This new proposal reconciles conceptual and empirical gaps encountered when clinical outcomes are compared to the pharmacology of antipsychotics.