Genetic variants of D2 but not D3 or D4 dopamine receptor gene are associated with rapid onset and poor prognosis of methamphetamine psychosis.
D2-like receptors are key targets for methamphetamine in the CNS, and their activation is an initial and indispensable effect in the induction of dependence and psychosis. It is possible that genetic variants of D2-like receptors may affect individual susceptibility to methamphetamine dependence and psychosis. To test this hypothesis, 6 putatively functional polymorphisms of D2-like receptors, -141C Ins/Del, Ser311Cys and TaqIA of the DRD2 gene, Ser9Gly of the DRD3 gene, and -521C>T and a variable number of tandem repeats in exon 3 of the DRD4 gene, were analyzed in 202 patients with methamphetamine dependence and/or psychosis and 243 healthy controls in a Japanese population. No polymorphism examined showed significant association with methamphetamine dependence, but two polymorphisms of DRD2 were associated with the clinical course and prognosis of methamphetamine psychosis. The A1/A1 homozygote of DRD2 was a negative risk factor for a poorer prognosis of psychosis that continues for more than 1 month after the discontinuance of methamphetamine abuse and the beginning of treatment with neuroleptics (p=0.04, odds ratio (OR)=0.42, 95% CI; 0.27-0.65) and the complication of spontaneous relapse of methamphetamine psychosis after remission (p=0.014, OR=0.34, 95% CI; 0.22-0.54). The genotype of -141C Del positive (Del/Del and Del/Ins) was at risk for rapid onset of methamphetamine psychosis that develops into a psychotic state within 3 years after initiation of methamphetamine abuse (p=0.00037, OR=3.62, 95% CI 2.48-5.28). These findings revealed that genetic variants of DRD2, but not DRD3 or DRD4, confer individual risks for rapid onset, prolonged duration, and spontaneous relapse of methamphetamine psychosis.
Ujike
Hiroshi
H
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. hujike@cc.okayama-u.ac.jp
Katsu
Takeshi
T
Okahisa
Yuko
Y
Takaki
Manabu
M
Kodama
Masafumi
M
Inada
Toshiya
T
Uchimura
Naohisa
N
Yamada
Mitsuhiko
M
Iwata
Nakao
N
Sora
Ichiro
I
Iyo
Masaomi
M
Ozaki
Norio
N
Kuroda
Shigetoshi
S
D000328:Adult; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D011379:Prognosis; D011605:Psychoses, Substance-Induced / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012694:Serine / Q000235:genetics; D018709:Statistics, Nonparametric
D000697:Central Nervous System Stimulants; C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D008694:Methamphetamine; D012694:Serine; D005998:Glycine