Receptor Binding Targets for Antipsychotic Efficacy

Abstract

In order to identify the contribution of individual serotonin and dopamine receptor subtype binding targets to antipsychotic medication efficacy, we analyzed correlations between binding affinity to cloned dopamine and serotonin receptor subtypes and clinically effective drug dose for atypical antipsychotic medications. The strongest correlation was observed between binding affinity to the D3 subtype dopamine receptor and clinically effective atypical antipsychotic medication drug dose (r = 0.77, p = 0.005). In contrast, binding affinity to the D2 (r = 0.59, p = 0.056) and D4 subtype dopamine receptors (r = 0.23, p = 0.23) exhibited lower correlations with atypical antipsychotic medication dosages. No direct correlations were identified between atypical antipsychotic medication dose and binding affinities to serotonin 5-HT1A, 5-HT2A, 5-HT2C, or 5-HT7 receptor subtypes. Highly significant correlations were also observed between atypical antipsychotic medication dose and the ratios of D2/5-HT1A (r = 0.69, p = 0.019); D3/5-HT1A (r = 0.69, p = 0.02); D3 × 5-HT2A (r = 0.71, p = 0.014); (D2 × D3)/5-HT1A (r = 0.81, p = 0.002); (D2 × D3 × 5-HT7)/5-HT1A (r = 0.74, p = 0.010); (D2 × D3 × 5-HT2A)/5-HT1A (r = 0.76, p = 0.007); (D2 × D3 × 5-HT2C)/5-HT1A (r = 0.76, p = 0.007); and (D2 × D3 × 5-HT2A × 5-HT2C)/5-HT1A (r = 0.72, p = 0.013) receptor binding affinities. These observations suggest opposing interactions among three distinct domains of receptor binding targets contribute to the antipsychotic effects of atypical antipsychotic medications: (1) D3 and D2 dopamine receptor binding affinity enhance atypical antipsychotic medication potency. (2) Binding affinity to serotonin 5-HT2A, 5-HT2C, and 5-HT7 receptors also facilitates antipsychotic efficacy. (3) In contrast, enhanced binding affinity to serotonin 5-HT1A receptor reduces antipsychotic medication potency.