Dopamine and serotonin receptor binding and antipsychotic efficacy

The relationship between clinically effective antipsychotic drug dosage and binding affinity to cloned dopamine (DA) and serotonin receptor subtypes was analyzed in an effort to elucidate the contribution of individual receptor subtypes to medication response. Clinically effective dose and binding affinity to D-2 DA receptor were modestly correlated for typical antipsychotic medications (r = 0.54, p = 0.046), but surprisingly were not correlated for atypical antipsychotics (r = 0.41, p = 0.31). For typical antipsychotics, a more robust inverse relationship was observed between medication dose and 5-HT2C affinity (r = -0.68, p = 0.021). The strongest correlation for typical antipsychotics was observed between drug dosage and 5-HT2C/D-2 binding affinity ratio (r = 0.81, p 0.003). For atypical antipsychotics, no significant correlations were identified between medication dosage and 5-HT2C, 5-HT2A, 5-HT2C/(D2), or 5-HT2A/D-2 receptor-binding affinities. In contrast, atypical antipsychotic medication dosage was highly correlated with the ratios of D2 (5-HT2A/5-HT1A) (r = 0.80, p = 0.031), and D-2 (5-HT2C/5-HT1A) (r = 0.78, p = 0.038) binding affinities. These observations demonstrate an interaction between D-2 and 5-HT2C receptor effects contributing to positive symptom response for typical antipsychotic medications, suggesting that signaling through 5-HT2C receptors interacts with and improves antipsychotic effects achieved via D-2 receptor blockade. This analysis also demonstrates that, in contrast to typical antipsychotics, therapeutic effects of atypical antipsychotic medications are determined by opposing interactions among three different domains: (1) increasing D-2 DA receptor- binding affinity enhances antipsychotic potency. (2) Increasing 5-HT2C and 5-HT2A receptor-binding affinities also facilitate antipsychotic efficacy. (3) Increasing 5-HT1A receptor-binding affinity, in contrast, reduces antipsychotic efficacy.