Identification of novel therapies for nicotine dependence that work in special populations with high smoking rates may both reduce the burden of smoking-related diseases in these populations and yield benefits applicable to smokers in the general population. Recent advances in understanding of smoking behavior identify the NMDA receptor complex as a potential pharmacotherapeutic target for smoking cessation. We hypothesize that tobacco-derived nicotine is self-therapeutic for individuals with schizophrenia, acting in part through improving NMDA glutamatergic hypoactivity, and that therapeutically increasing NMDA activity in these patients would reduce their smoking drive and improve smoking cessation rates. We further hypothesize that such effects may be mediated by ameliorating cognitive dysfunction and by improving the impaired reward function in schizophrenia patients known as negative symptoms. Sarcosine, an inhibitor of the GlyT1 and system A glycine transporters that regulate synaptic concentrations of the essential NMDA co- agonist, glycine, recently has been demonstrated to be therapeutic for negative symptoms and cognitive dysfunction in schizophrenia. This effect is attributed to augmenting extracellular levels of glycine. We propose to conduct a clinical trial to assess the sarcosine's therapeutic potential to promote smoking cessation in individuals with schizophrenia. As part of this study, we will, in the clinical setting, explore associations between clinical response and changes in negative symptoms, cognitive function, reward responsivity and brain glycine concentration. The imaging component at McLean Hospital will be comprised of scanning subjects being treated with either sarcosine or placebo for magnetic resonance spectroscopy (MRS) studies of brain glycine that will be used to determine whether baseline glycine levels are predictive of treatment response, smoking severity, and severity of schizophrenic symptoms. Glycine measurements during and at the end of therapy will be used to determine whether sarcosine increases brain glycine and whether the magnitude of brain glycine increase correlates with cigarette use and craving. This study follows a series of studies by the investigators to utilize glycine agonists to improve negative symptoms and cognitive function of schizophrenia, to test therapies for nicotine dependence in schizophrenia and to improve MRS techniques for measurement of brain glycine.
