Affiliation:
1. Institute of Neurosciences of Castilla y Leon (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, (Group GIR-BMD), University of Salamanca, 37007-Salamanca, Spain
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-
HT2A 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.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmacology
Cited by
6 articles.
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