Short allele of 5-HTTLPR as a risk factor for the development of psychosis in Japanese methamphetamine abusers

Norikazu Ezaki, Kazuhiko Nakamura, Yoshimoto Sekine, Ismail Thanseem, Ayyappan Anitha, Yasuhide Iwata, Masayoshi Kawai, Kiyokazu Takebayashi, Katsuaki Suzuki, Nori Takei, Masaomi Iyo, Toshiya Inada, Nakao Iwata, Mutsuo Harano, Tokutaro Komiyama, Mitsuhiko Yamada, Ichiro Sora, Hiroshi Ujike, Norio Mori

Research output: Chapter in Book/Report/Conference proceedingConference contribution

21 Citations (Scopus)


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-HT1A 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-HT1A 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.

Original languageEnglish
Title of host publicationDrug Addiction
Subtitle of host publicationResearch Frontiers and Treatment Advances
PublisherBlackwell Publishing Inc.
Number of pages8
ISBN (Print)9781573317184
Publication statusPublished - 10-2008

Publication series

NameAnnals of the New York Academy of Sciences
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science


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