Grant: CIHR Clinician Scientist - Phase 2

Schizophrenia is a serious and prevalent mental illness that affects approximately 1% of Canadians and is characterized by a number of symptoms, such as disorganization, unusual beliefs and poor cognitive functioning. The brain mechanisms that lead to schizophrenia are poorly understood; however, recent studies suggest that impaired brain inhibition may be involved in the development of psychotic symptoms in schizophrenia. Inhibition refers to a brain process that filters out excessive information in the environment, so that information can be processed effectively. Clozapine - one of the most effective medications used to treat schizophrenia - has also been related to brain inhibition. Our recent studies using transcranial magnetic stimulation have shown that clozapine results in a significant increase in brain inhibition when compared to other antipsychotic medications. This increase in brain inhibition is also accompanied by neurophysiological changes which suggest that GABAB - a specific brain receptor - is increased. Our preliminary molecular experiments also suggest that clozapine enhances brain inhibition by acting directly on the GABAB receptor. In this proposal, we intend to further our understanding of this promising data through experiments that will investigate the effects of clozapine on brain inhibition, as compared to other antipsychotic medication, in brain regions that are most affected in this disorder. We will also investigate the genetic basis of this response. These studies may ultimately help us to better understand the brain mechanisms involved in schizophrenia, as well as potentially provide new pathways through which future medications may be developed to treat this devastating disorder.