Variation in dopamine D2 and serotonin 5-HT2A receptor genes is associated with working memory processing and response to treatment with antipsychotics
Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with
antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these
phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal
working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T
allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics
compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect
on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration
antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the
rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the
attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during
working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment
in two independent samples of patients with schizophrenia (n¼63 and n¼54, respectively), consistent with the previously reported
separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological
prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that
further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships
