Neurobiology of response to clozapine in treatment resistant schizophrenia

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The aim of this research is to understand how Clozapine, a drug used to treat schizophrenia, produces its therapeutic effects. Clozapine is normally only used in very unwell patients, who have already tried other medications which have not worked. This is because, although clozapine is the most effective treatment for schizophrenia, it can also cause serious side effects. Patients taking clozapine are therefore closely monitored, including having regular blood tests. Unfortunately clozapine is only effective in reducing symptoms in about half of patients who try it, and there are very few treatment options left for patients who do not do well on clozapine. For these reasons, many doctors and patients put-off trying clozapine, only using it as a last resort. During this delay, patients are often treated instead with high doses of other medications or several medications in combination, which is not proven to be a good strategy and may also be harmful. At the moment, it is unknown how clozapine produces its therapeutic effects and why it works better in some people than in others. In this project, we will try and understand the biology behind the therapeutic effects of clozapine. We hope that understanding the biology will help scientists develop new medications as alternatives to clozapine, which could be used in patients who do not get better with clozapine or who experience bad side effects. We also hope that understanding the biology behind the effects of clozapine will help us to develop tests to predict in advance whether or not an individual patient is likely to get better with clozapine treatment. Such a test would mean that clozapine might be given earlier to patients who are likely to do well on it, while it could be avoided in patients who are unlikely to benefit. We think that the therapeutic effects of clozapine might be due to its ability to improve chemical signalling in the brain. On the basis of previous research, we are particularly interested in the effects of clozapine on two closely related chemicals which are vital for normal brain functioning - glutamate and GABA (gamma-amino-butyric-acid). We also think that the response to clozapine will be associated with specific patterns of blood flow in the brain. Using magnetic resonance imaging (MRI) brain scans, we are able to measure the amounts of glutamate and GABA and blood flow non-invasively in patients. In this project, we will use MRI scans to measure brain glutamate, GABA and perfusion in patients with schizophrenia before they start clozapine treatment and after they have been taking clozapine for 12 weeks, as part of their normal clinical care. We will assess each patients' symptoms before and after 12 weeks of clozapine to see how well their symptoms have improved. By looking at the changes in glutamate, GABA and blood flow in the brain which occur with clozapine treatment in relation to change in symptoms, we will better understand how clozapine produces its therapeutic effects. We will also be able to determine whether the level of glutamate, GABA and pattern of blood flow in the brain before starting clozapine can predict whether or not clozapine will improve symptoms in a particular patient.We hope that this information will then be useful to developing new drugs for schizophrenia, for example drugs with greater effects on brain glutamate, GABA and blood flow. We also hope that this research could lead to tests, where MRI scans measuring glutamate, GABA and blood flow could help doctors decide whether or not clozapine might be effective in their individual patient, where a positive result would encourage them to try it earlier. In these ways, this research could improve the health of patients with schizophrenic illness.