Vulnerable combinations of functional dopaminergic polymorphisms to late-onset treatment resistant schizophrenia.

Abstract

BACKGROUND:

A significant portion of patients with schizophrenia who respond to initial antipsychotic treatment acquire treatment resistance. One of the possible pathogeneses of treatment-resistant schizophrenia (TRS) is antipsychotic-induced dopamine supersensitivity psychosis (Ai-DSP). Patients with this disease progression might share some genetic vulnerabilities, and thus determining individuals with higher risks of developing Ai-DSP could contribute to preventing iatrogenic development of TRS. Therefore, we decided to examine whether combinations of functional single nucleotide polymorphisms (SNPs) known to affect dopaminergic functions are related to Ai-DSP development.

METHODS:

In this case-control study, 357 Japanese participants diagnosed with schizophrenia or schizoaffective disorder were recruited and divided into two groups, those with and without Ai-DSP. As functional SNPs, we examined rs10770141 of the tyrosine hydroxylase gene, rs4680 of the catechol-O-methyltransferase gene, and rs1799732 and rs1800497 of the DRD2 genes, which are known to possess strong directional ties to dopamine synthesis, dopamine degradation and post-synaptic DRD2 prevalence, respectively.

RESULTS:

Among the 357 Japanese patients with schizophrenia or schizoaffective disorder, 130 were classified as Ai-DSP(+) and the other 227 as Ai-DSP(-). Significantly higher proportions of Ai-DSP(+) patients were found to have the SNP combinations of rs10770141/rs4680 (57.9%, OR2.654, 95%CI1.036-6.787, P = 0.048) and rs10770141/rs4680/ rs1800497 (64.3%, OR4.230, 95%CI1.306-13.619, P = 0.029). However, no single SNP was associated with Ai-DSP.

CONCLUSIONS:

We preliminarily found that carrying particular combinations of functional SNPs, which are related to relatively higher dopamine synthesis and dopamine degradation and lower naïve DRD2, might indicate vulnerability to development of Ai-DSP. However, further studies are needed to validate the present results.

• Authors: Kengo Oishi, Nobuhisa Kanahara, Masayuki Takase, Yasunori Oda, Yusuke Nakata, Tomihisa Niitsu, Masatomo Ishikawa, Yasunori Sato, Masaomi Iyo
• Journal: PloS one (PLoS One) Vol. 13 Issue 11 Pg. e0207133 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 30408108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• DRD2 protein, human
• Receptors, Dopamine D2
• Tyrosine 3-Monooxygenase
• COMT protein, human
• Catechol O-Methyltransferase

Topics

• Adolescent
• Adult
• Age of Onset
• Aged
• Aged, 80 and over
• Antipsychotic Agents (therapeutic use)
• Case-Control Studies
• Catechol O-Methyltransferase (genetics)
• Drug Resistance (genetics)
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Male
• Middle Aged
• Pharmacogenomic Variants
• Polymorphism, Single Nucleotide
• Preliminary Data
• Psychotic Disorders (drug therapy, epidemiology, genetics)
• Receptors, Dopamine D2 (genetics)
• Schizophrenia (drug therapy, epidemiology, genetics)
• Tyrosine 3-Monooxygenase (genetics)
• Young Adult