A double-blind, placebo-controlled trial of the NMDA glycine site antagonist, GW468816, for prevention of relapse to smoking in females.

Dependence on tobacco-derived nicotine accounts for more than 440,000 deaths, 5.1 million years of potential life lost, and $96.8 billion in productivity losses annually in the United States.1,2 The health impact of tobacco dependence on health is on the rise, whereas there were 100 million deaths worldwide in the 20th century caused by tobacco. If current trends continue, there will be 1 billion in the 21st century.3 Although effective pharmacotherapies exist that double or triple cessation rates when combined with behavioral therapy,4,5 relapse rates are very high, with sustained 1-year abstinence rates of less than 25% among those who attained initial abstinence, even with the best treatment available.6-12 Thus, we face a critical need to develop relapse prevention treatments that help smokers to sustain abstinence. Nicotine dependence, like other addictions, is a chronic relapsing disorder. Although neurobiologic mechanisms underlying relapse to smoking have not been elucidated, it is known that relapse is associated with postquit craving, postquit negative affect, depressed mood, hyper-reactivity to environmental cues associated with smoking use, and stress.13-17 Effective relapse prevention treatment may require unique behavioral and pharmacological interventions that differ from those currently available for smoking cessation. Nicotine acts as an agonist at presynaptic and postsynaptic receptors on both dopaminergic and glutamatergic neurons in the neural circuitry involved in motivational, emotional, and cognitive processes relevant to goal-directed behaviors such as drug seeking, and recent work suggests a role for glutamate and the ionotropic N-methyl-d-aspartate (NMDA) glutamate receptor in mediating relapse to drug use.18-30 N-methyl-d-aspartate receptors require binding of both glycine and glutamate for activation. N-methyl-d-aspartate antagonists acting at nonglycine sites on the receptor block chronic effects of opiates, alcohol, psychomotor stimulants, and nicotine.31-35 However, significant adverse effects on learning and motor coordination limit the therapeutic application of this approach, and glycine site antagonists offer an alternative to moderate NMDA receptor function that are better tolerated.36-38 A tetrahydroquinolinic derivative family of compounds active as competitive antagonists at the strychnine-insensitive glycine site on the NMDA receptor was developed by GlaxoSmithKline (GSK).39 One of these compounds, GW468816 (Fig. 1, compound 2a on Di Fabio et al39), has shown potential efficacy for prevention of relapse to nicotine-seeking behavior in short- and long-term preclinical abstinence models (GSK reports VR2000/00020/00 and VR2000/00026/00). In these studies, GW468816 reduced nicotine-cue and nicotine-priming–induced reinstatement of drug use after a period of abstinence in a rat model of nicotine self-administration without inducing motor side effects, suggesting potential efficacy under conditions known to trigger relapse to smoking. GW468816, in a range of oral doses (0.01–1 mg/kg), also demonstrated efficacy at reducing craving and withdrawal symptoms in preliminary human studies in abstinent smokers (GSK report VM2002/00022/00, study RES11015, 2002). FIGURE 1 Kaplan-Meier survival curves for the active and placebo groups. To test the hypothesis that glycine-dependent modulation of NMDA receptors may reduce relapse, we conducted a 5-week double-blind, placebo-controlled trial of GW468816 in recently abstinent adult female smokers. Our primary hypotheses were that compared with those assigned to placebo, smokers assigned to GW468816 would (1) achieve a higher rate of 7-day point prevalence abstinence at the end of the 5-week relapse prevention phase, and (2) demonstrate a significantly longer time to relapse over a 60-day follow-up.