[A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine].

Autor:	Kibitov АО; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Krupitsky ЕМ; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Blokhina ЕА; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Verbitskaya ЕV; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Brodyansky VМ; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Alekseeva NP; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Bushara NМ; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Yaroslavtseva ТS; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Palatkin VY; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Masalov DV; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Burakov АМ; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Romanova ТN; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Sulimov GY; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Grinenko AY; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Kosten Т; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Nielsen D; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia., Zvartau EE; Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
Jazyk:	ruština
Zdroj:	Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova [Zh Nevrol Psikhiatr Im S S Korsakova] 2016; Vol. 116 (11. Vyp. 2), pp. 36-48.
DOI:	10.17116/jnevro201611611236-48
Abstrakt:	Aim: To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial. Material and Methods: Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine. Results: The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p<0.0125). Conclusion: The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.
Databáze:	MEDLINE
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