Role of serotonin and dopamine receptor binding in antipsychotic efficacy

In an effort to analyse the contribution of individual serotonin and dopamine receptor subtypes to antipsychotic medication response, we analysed the correlation between clinically effective antipsychotic drug dose and binding affinity to cloned serotonin and dopamine receptor subtypes. Clinically effective dosage and binding affinity to the D(2) dopamine receptor subtype were moderately correlated for typical antipsychotic medications (r=0.57, p=0.04), and were similarly modestly correlated for atypical antipsychotic drugs (r=0.66, p=0.07). Surprisingly for typical antipsychotic medications, a stronger inverse correlation was observed between drug dosage and 5-HT(2C) affinity (r=-0.65, p=0.03). The strongest correlation observed for typical antipsychotic medications was between medication dose and 5-HT(2C)/D(2) binding affinity ratio (r=-0.81, p=0.002). For atypical antipsychotic medications, highly significant correlations were observed between medication dose and receptor-binding affinity to D(3) dopamine receptor (r=0.78, p=0.02), and with the ratios of D(2)/5-HT(1A) (r=0.85, p=0.009), D(3)/5-HT(1A) (r=0.78, p=0.021), D(2) (5-HT(2A)/5-HT(1A)) (r=0.75, p=0.033) and D(3) (5-HT(2A)/5-HT(1A)) (r=0.75, p=0.03) receptor-binding affinities. The correlation between medication dose and D(2) (5-HT(2C)/5-HT(1A)) receptor-binding affinity ratio was of similar magnitude (r=0.70, p=0.055). No significant correlations were identified between atypical antipsychotic medication dose and 5-HT(1A), 5-HT(2A), 5-HT(2C), 5-HT(2C)/D(2) or 5-HT(2A)/D(2) receptor-binding affinities. These observations suggest an interaction between D(2) and 5-HT(2C) receptor-binding effects contributing to the therapeutic response achieved following treatment with typical antipsychotic medications. This suggests that for typical antipsychotic medications, constitutive serotonin 5-HT(2C) receptor signalling interacts with and facilitates the antipsychotic benefit achieved through dopamine D(2) receptor blockade. Additionally, this analysis demonstrates that, in contrast to typical antipsychotic medications, the therapeutic effectiveness of atypical antipsychotic medications results from opposing interactions among three distinct domains: (1) antipsychotic potency is enhanced by increased D(2) and D(3) dopamine receptor-binding affinity; (2) antipsychotic efficacy is also facilitated by increased binding affinity to serotonin 5-HT(2C) and 5-HT(2A) receptors; (3) in contrast, antipsychotic potency is reduced by elevations in 5-HT(1A) receptor-binding affinity.