Pathway-assisted investigation of atypical antipsychotic drugs and serotonin receptors in schizophrenia

Clozapine and its four related drugs (olanzapine, quetiapine, risperidone and ziprasidone) are the most frequently used treatments for schizophrenia in the world. The underlying mechanisms are not well understood. In this study, we investigated the features of these five drugs through their related genes at the pathway level. For each drug, we first identified pathways that the drugs might be involved in. We found that these five drugs are all significantly involved in five pathways, i.e., G-protein coupled receptor signaling, cAMPmediated signaling, serotonin receptor (5-HT) signaling, AMPK signaling, and cardiac hypertrophy signaling. Among these pathways, the serotonin receptor (5-HTR) pathway is an important neurotransmitter-related pathway implicated in psychiatric disorders. Therefore, we further investigated the functional relationship between these five drugs and serotonin receptors based on the experimental data of activation, chemical-protein interaction, expression, inhabitation, and binding regulation. We constructed a drug-5-HTR network including these five drugs, serotonin receptors, and their relationships and found that clozapine has more interactors and more complicated connections with serotonin receptors than the other four drugs. Additionally, clozapine has two unique relationships with HTR2A, one of the most susceptible candidate genes for schizophrenia. These results indicated that clozapine might have a different action during the treatment process of schizophrenia from the other four drugs.