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Short Allele of 5‐HTTLPR as a Risk Factor for the Development of Psychosis in Japanese Methamphetamine Abusers
Author(s) -
Ezaki Norikazu,
Nakamura Kazuhiko,
Sekine Yoshimoto,
Thanseem Ismail,
Anitha Ayyappan,
Iwata Yasuhide,
Kawai Masayoshi,
Takebayashi Kiyokazu,
Suzuki Katsuaki,
Takei Nori,
Iyo Masaomi,
Inada Toshiya,
Iwata Nakao,
Harano Mutsuo,
Komiyama Tokutaro,
Yamada Mitsuhiko,
Sora Ichiro,
Ujike Hiroshi,
Mori Norio
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1432.011
Subject(s) - psychosis , serotonin transporter , serotonergic , methamphetamine , 5 httlpr , allele , genotype , psychology , medicine , psychiatry , genetics , biology , serotonin , receptor , gene
Accumulating evidence suggests that genetic factors contribute to the vulnerability to methamphetamine (MAP) abuse and associated psychiatric symptoms. Chronic MAP abuse leads to psychosis, which may be of a transient or a prolonged type. Serotonergic dysfunction has been proposed as one of the contributory factors in the development of MAP psychosis. Our PET studies revealed that the serotonin transporter (5‐HTT) density in global brain regions is significantly lower in MAP abusers. In this study, we examined the role of a functional polymorphism in the 5′ flanking region of the 5‐HTT gene (5‐HTTLPR) in the development of MAP psychosis in a Japanese population. We analyzed DNA samples from 166 MAP patients (95 with transient and 71 with prolonged psychosis) and 197 age‐, sex‐, and geographic‐origin‐matched healthy controls. Patients were also subdivided according to the presence ( n = 119) or absence ( n = 148) of spontaneous relapse. We observed significant genotypic association of the 5‐HTTLPR polymorphism with MAP psychosis ( P = 0.022), particularly in patients who show prolonged psychosis. The frequency of the S allele in patients with prolonged psychosis was significantly higher than that of the controls ( P = 0.045); it was further higher in patients with prolonged psychosis with spontaneous relapse ( P = 0.004). 5‐HTTLPR has been suggested to regulate the transcriptional activity of 5‐HTT , with S alleles showing lesser transcriptional efficiency and also lower 5‐HT 1A receptor‐binding potential. Prolonged MAP use, combined with the high frequency of 5‐HTTLPR S‐alleles, may lead to reduced 5‐HTT levels and 5‐HT 1A receptor‐binding potential in the brain, resulting in the dysfunction of the serotonergic system. Thus, we suggest a possible role for the 5‐HTTLPR polymorphism in MAP psychosis.