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

Abstract

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.

A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter

“…Specifically, increased tonic synaptic levels of dopamine in the striatum following the initial treatment with APDs would determine the stimulation of a dopamine D 2 receptor reserve, which is defined as the difference between the total number of available D 2 receptors (100%) and the proportion of those D 2 receptors bound by an APD at a dose within the therapeutic window (60-80% blockade of central D 2 receptors). The receptor reserve primarily includes presynaptic dopamine receptors, which tonically inhibit dopamine synthesis and release, and may mediate antipsychotic effects [5]. Present results showing an early suppression of mRNA DAT expression (Fig.…”

“…By contrast, decreased tonic synaptic availability of dopamine, occurring during chronic APD treatment, is associated with a significant loss of APD efficacy. These effects may reflect a reduced stimulation of the D 2 receptor reserve triggered by the initial treatment [5]. Notably, dopamine release in the striatum is closely related to the firing of dopaminergic neurons in the midbrain, which was decreased in this study (Fig.…”

“…It is often suggested that the maximal clinical response is achieved when APDs block~65-75% of D 2 receptors and is negligible when D 2 receptor occupancy is below this therapeutic window [3,4]. However, a growing body of evidence appears to cast doubt on the causal effect of this mechanism [5]. Although antipsychotic therapeutic efficacy may appear positively associated with receptor blockade at the beginning of the treatment, APDs exhibit declining therapeutic efficacy with long-term treatment even though their receptor occupancy remains fairly stable.…”

Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment

“…All antipsychotic drugs interact with dopamine D2 receptors 13 , with variable ranges of D2 occupacy suggested to be important for optimal clinical and cognitive responses 13 – 15 . From a pharmacokinetic perspective, genetic variations such as those in CYP2D6 , CYP3A4/5 , and ABCB1 might impact the metabolism and distribution of antipsychotic drugs, potentially affecting the margin between the dosages that are required for efficacy and those associated with side effects 16 , 17 .…”

Neuronal signature of an antipsychotic response

“…Antipsychotic drugs (APDs) are widely used to treat psychosis in schizophrenia 1,2 and symptoms in other neuropsychiatric conditions 3 . Blocking dopamine signaling onto 60-80% of striatal D2 receptors (D2r) is thought to underlie their therapeutic efficacy 4,5 .…”