Effect of Memantine on ERP in Early Schizophrenia and Healthy Subjects

In this proposal, we use one-dose memantine trial to compare the difference of MMN change between healthy subjects and early schizophrenia patients. The cognitive and negative symptoms will be counted as possible confounding variables. We would like to make connection and association between neurobiological and neurocognitive markers for further treatment application. The specific aim of this project is to test if memantine will influence the ERPs change, as in healthy subjects, in patients with early schizophrenia. The specific study population is been known of just have their first episode psychosis subsided, conventionally defined by significantly improved positive symptoms, yet some of them complaining of cognitive decline or presenting with persistent negative symptoms. Previous study showed improvement in mismatch negativity was correlated with general function improvement in schizophrenia. Although a recent study failed to demonstrate positive effects on residual psychopathology of a group of chronic stable schizophrenic patients. In this study we are targeting at a specific population of early schizophrenic patients to examine the efficacy of memantine on neurobiological markers and possible application to general psychopathology. Our objectives include: 1. Test memantine effects on the change of ERPs, especially focus on mismatch negativity. 2. Compare the ERP difference between healthy subjects and early schizophrenic patients 3. Examine whether the effect of memantine will be affected by any significant baseline clinical variables or predisposed cognitive deficits. First if we could replicate the ERP change in healthy subjects influenced by memantine, and we could further compare the difference between healthy subjects and patient subjects. It may support the hypothesis of NMDA-type glutamate receptor dysregulation theory in schizophrenia. If further association is detected through larger scale study between ERP and clinical symptoms, we could apply memantine in the add-on treatment of schizophrenia. As memantine is already an approved medicine for treatment of moderate to severe Alzheimer disease in many countries worldwide, hopefully we can add a new indication to its original clinical application. Thus it will become the first medicine that can help a condition which has rendered a lot of schizophrenic patients marked impairments in their social and occupational functioning from the early stage of their life. We believe this impact will be even bigger than the original indication of memantine, which is exclusively for patients with dementia. Rather than delaying deterioration of cognitive functioning in patient's late life, an adjuvant therapy for early intervention in schizophrenia aiming at improving cognitive function and hence restoring social and occupational functioning bears greater impact on a patient's life trajectory and lessen the burden of a society. Furthermore, the results from this project will provide critical evidence to support or refute the hypoglutaminergic theory of schizophrenia, which might be an important complement to the hyperdopaminergic theory. With a better understanding of the pathophysiology of schizophrenia not only focusing on dopaminergic system-related positive symptoms but also glutamatergic system-related cognitive and negative symptoms, will provide theoretic base of psychopharmacology in developing agents targeting at different systems to improve the outcome of schizophrenia from the early stage or even the putative pre-psychotic stage of the illness.