AUTHOR=Kogure Masanobu , Kanahara Nobuhisa , Miyazawa Atsuhiro , Shiko Yuki , Otsuka Ikuo , Matsuyama Koichi , Takase Masayuki , Kimura Makoto , Kimura Hiroshi , Ota Kiyomitsu , Idemoto Keita , Tamura Masaki , Oda Yasunori , Yoshida Taisuke , Okazaki Satoshi , Yamasaki Fumiaki , Nakata Yusuke , Watanabe Yoshinori , Niitsu Tomihisa , Hishimoto Akitoyo , Iyo Masaomi 

TITLE=Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

JOURNAL=Frontiers in Psychiatry

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1334335

DOI=10.3389/fpsyt.2023.1334335

ISSN=1664-0640

ABSTRACT=<sec id="sec1"><title>Background</title><p>Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways.</p></sec><sec id="sec2"><title>Patients and methods</title><p>To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, <italic>n</italic> = 435; non-TRS, <italic>n</italic> = 539) and healthy controls (HC: <italic>n</italic> = 489).</p></sec><sec id="sec3"><title>Results</title><p>The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on <italic>SLC6A3</italic> differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of <italic>COMT</italic> and <italic>SLC6A3</italic> yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology.</p></sec><sec id="sec4"><title>Conclusion</title><p>The overall results suggest that (<italic>i</italic>) <italic>SLC6A3</italic> could be involved in responsiveness to antipsychotic medication and (<italic>ii</italic>) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.</p></sec>