title: A double-blind, placebo-controlled trial of the NMDA glycine site antagonist, GW468816, for prevention of relapse to smoking in females.
abstract: Relapse to smoking is common after initial abstinence with pharmacotherapy and behavioral support and represents a major clinical challenge. Although mechanisms underlying relapse to smoking have not been elucidated, preclinical studies suggest that glutamate receptors may be involved. We sought to test a selective antagonist of the glycine coagonist site on the glutamate N-methyl-D-aspartate receptor, GW468816, for prevention of relapse in recently abstinent smokers. To do so, we enrolled 264 healthy female smokers in an open 8-week smoking cessation intervention with behavioral therapy and a standard dose of transdermal nicotine replacement therapy with taper and additional gum or lozenge as needed for nicotine withdrawal symptoms. Ninety-eight participants achieved 7-day point prevalence abstinence and were randomized into a 5-week double-blind, placebo-controlled, relapse-prevention trial of GW468816 (200 mg/d) and then followed for 60 days after randomization. There was no effect of treatment on abstinence rates at the end of treatment (χ² [1, n = 96] = 0.168, P = 0.838), on the rates of relapse (χ² [1, n = 98] = 0.031, P = 1.000) or lapse (χ² [1, n = 62] = 0.802, P = 0.423), or on time to relapse (χ² [1, n = 98) = 0.001, P = 0.972). No significant relationships were detected between plasma GW468816 concentrations and abstinence, time to relapse, or self-reported craving. In conclusion, despite promising preclinical data that support the use of a selective NMDA glycine site antagonist for prevention of relapse to smoking, we observed no effect of GW468816 on relapse or lapse rates, time to relapse, or craving compared to placebo.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA. a_eden_evins@hms.harvard.edu
authors.forename: A Eden
authors.initials: AE
authors.lastname: Evins
authors.forename: Gladys
authors.initials: G
authors.lastname: Pachas
authors.forename: David
authors.initials: D
authors.lastname: Mischoulon
authors.forename: Karen
authors.initials: K
authors.lastname: Urbanoski
authors.forename: Sara
authors.initials: S
authors.lastname: Carlini
authors.forename: Jessica
authors.initials: J
authors.lastname: Sousa
authors.forename: Kate
authors.initials: K
authors.lastname: Bentley
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Rigotti
authors.forename: Johanna
authors.initials: J
authors.lastname: Nino-Gomez
authors.forename: Tsafrir
authors.initials: T
authors.lastname: Loebl
authors.forename: Amy C
authors.initials: AC
authors.lastname: Janes
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Kaufman
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D005260:Female; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D055502:Secondary Prevention; D016540:Smoking Cessation / Q000379:methods*; D000074606:Smoking Prevention; D013997:Time Factors; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder / Q000534:rehabilitation; D016896:Treatment Outcome
chemical_list: C568841:GW 468816; D011759:Pyrrolidines; D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine