Risk Genes in Schizophrenia and Their Importance in Choosing the Appropriate Antipsychotic Treatment

Title:Risk Genes in Schizophrenia and Their Importance in Choosing the Appropriate Antipsychotic Treatment

Volume: 27 Issue: 30

Author(s): Felix-Martin Werner*Rafael Coveñas*

Affiliation:

• Institute of Neurosciences of Castilla y Leon (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, (Group GIR-BMD), University of Salamanca, 37007-Salamanca,Spain

• Institute of Neurosciences of Castilla y Leon (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, (Group GIR-BMD), University of Salamanca, 37007-Salamanca,Spain

Keywords: Antipsychotic drug, cholecystokinin, D₂ receptor, D₃ receptor, dopamine, dysbindin-1, GABA, GAD 67, glutamate, hippocampus, neuregulin-1, prefrontal cortex, risperidone, serotonin, single nucleotide polymorphism, susceptibility gene, ventral tegmental area.

Abstract:

Background: Schizophrenia is a chronic mental illness that in 80% of cases has a genetic etiology. In the last years, 260 risk genes with a predisposition to schizophrenia have been discovered and correlations between risk genes and the therapeutic efficacy of an antipsychotic treatment/pharmacotherapy resistance have been reported.

Objective: The objective of this review is to update the main risk genes involved in schizophrenia and to establish an association between the single nucleotide polymorphisms (SNPs) of these genes and pharmacotherapy resistance/efficacy of a determined antipsychotic treatment. Besides, neural networks in the brain centers involved in schizophrenia will be updated to point out the altered functions of classical neurotransmitters and neuropeptides due to risk genes.

Methods: In schizophrenia, important risk genes, such as catechol-O-methyl transferase (COMT), monoamine oxidase (MAO A/B), glutamic acid decarboxylase 67 (GAD 67), dysbindin-1 and neuregulin-1 will be mentioned. To describe the function of these risk genes, neural networks in the ventral tegmental area, hippocampus and prefrontal cortex will also be developed.

Results: An association between the SNPs of some risk genes and the efficacy of an antipsychotic treatment is reported: SNPs such as rs165599 (COMT gene), rs1801028 (D₂ receptor gene) and rsSer⁹Gly (D₃ receptor gene) are associated with a better antipsychotic treatment efficacy (e.g., treatment of negative schizophrenic symptoms with risperidone). The rs4680 SNP (COMT and D₂ receptor genes) is associated with antipsychoticinduced dopamine hypersensitivity and pharmacotherapy resistance. The function of risk genes is described: COMT and MAO A/B genes, with reduced activity in the corresponding enzymes, are associated with a decrease in dopamine degradation and hence dopamine hyperactivity occurred via D₂ receptors. The GAD 67 risk gene is linked with GABAergic dysfunction and consequently GABAergic neurons weakly presynaptically inhibit D₂ dopaminergic neurons. The D-amino acid oxidase activator (DAOA) risk gene is connected with glutamatergic dysfunction via NMDA receptors. Glutamatergic neurons might exert a weak presynaptic inhibition upon 5- HT_2A serotonergic neurons located in the ventral tegmental area and hippocampus. Neural networks in the latter two regions and in the prefrontal cortex are updated.

Conclusion: It is important to examine the SNPs of the risk genes involved in schizophrenia to establish a correlation between these SNPs and the efficacy of a determined antipsychotic drug. In the future, after examining these SNPs, it might be possible to choose the most appropriate antipsychotic drug. Thus, schizophrenic patients with a good response to a determined antipsychotic treatment and patients with resistance to this treatment could be well differentiated.

Cite this article as:

Werner Felix-Martin *, Coveñas Rafael *, Risk Genes in Schizophrenia and Their Importance in Choosing the Appropriate Antipsychotic Treatment, Current Pharmaceutical Design 2021; 27 (30) . https://dx.doi.org/10.2174/1381612827666210215151333