Neurochemical and Clinical Effects of Glutamate Modulation in Schizophrenia

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Schizophrenia (SCZ) is a prevalent illness that is associated with significant disability and burden. Antipsychotic medications are the only approved pharmacological treatments. However, most patients are partially responsive or wholly unresponsive to them, and those that do respond are frequently burdened by significant side effects that limit compliance. Thus, newer treatments for SCZ are critically needed. All currently approved antipsychotic medications function primarily by blocking D2-type dopamine receptors. In contrast, recent alternative neurochemical theories focus on disturbances in brain glutamatergic pathways. While optimal approaches for normalization of glutamatergic function are currently under development and reflect significant progress in understanding the role of glutamate in the pathophysiology of SCZ, the rate of therapeutic development has been slow. One contributing factor to this lag is the lack of brain imaging-based biological markers by which researchers can determine the effects of experimental glutamatergic medications on the brain in SCZ. We propose to use Magnetic Resonance Spectroscopy (MRS) to assess the effects of a glutamatergic drug, N-acetylcysteine (NAC), on the brain. NAC is a precursor to glutathione (GSH), an antioxidant compound with glutamatergic effects that has been reported to improve symptoms in SCZ. Critical to the choice of NAC is that in preclinical studies it exhibits the same ability to block the PCP-induced glutamate surge as other agents under active development for therapy. Furthermore, abnormalities in medial prefrontal cortex (mPFC) glutamate (Glu) and GSH have been reported in medication-free individuals with SCZ. The potential for NAC challenge to restore these neurochemicals to normal levels presents a valuable opportunity to assess the effects of NAC on glutamatergic modulation in SCZ. To do so, we propose to recruit 20 antipsychotic naive individuals with SCZ and 20 matched healthy control subjects and perform MRS imaging measurements of Glu and GSH in the mPFC before and after NAC challenge. We hypothesize that NAC challenge will lead to amelioration of baseline abnormalities in these neurochemicals in SCZ, while no changes will be observed in healthy control subjects. We will also obtain clinical measures of positive, negative, and cognitive symptoms in these subjects. The proposed challenge design addresses the need for an imaging measure of engagement of the glutamate system by a putative glutamatergic therapeutic agent, which at present is lacking. This study could lay the groundwork for evaluating the efficacy of new treatments, by comparing this effect with clinical efficacy in chronic administration. Therefore, the present study could have a substantial impact on the imaging field and potentially provide a new tool to study the effects of glutamatergic agents on the brain, thereby increasing the effectiveness of drug development paradigms.