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Neurosci Biobehav Rev. 2018 Feb;85:146-159. doi: 10.1016/j.neubiorev.2017.09.027. Epub 2017 Sep 29.

Dopamine, the antipsychotic molecule: A perspective on mechanisms underlying antipsychotic response variability.

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Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA; Department of Psychiatry and Psychotherapy University Clinic, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany. Electronic address:
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, UK.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.


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.


Antipsychotics; Dopamine D2 receptors; Endogenous dopamine; Indirect agonism; Pharmacogenetics; Schizophrenia; Therapeutic variability; Treatment efficacy and failure

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