Neurobiology of response to clozapine in treatment resistant schizophrenia

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.

The aim of this research is to understand the neurobiology of response to clozapine in treatment resistant schizophrenia (TRS), as this will aid future drug development and support earlier clozapine initiation in patients most likely to benefit.

Our recent research suggests that TRS may be associated with increased glutamate levels in the anterior cingulate cortex, which may explain why dopaminergic antipsychotics fail in these patients. There is some evidence that clozapine may alter brain glutamatergic and GABAergic neurotransmission, but this has never been tested directly.
We hypothesise that response to clozapine in TRS will be associated with increases in GABA, decreases in brain glutamate levels and decreases in regional brain perfusion. Our secondary hypothesis is that patients with the lowest GABA and perfusion and highest glutamate levels before starting clozapine will show the greatest response to treatment.

The sample will include 60 patients with TRS. All data will be acquired before and after 12 weeks of clozapine treatment. Regional brain glutamate and GABA levels will be estimated using proton magnetic resonance spectroscopy (1H-MRS), and perfusion using pulsed continuous arterial spin labelling (pCASL) in a single MRI scanning session. Severity of schizophrenia symptoms will be assessed, primarily using the positive and negative syndrome scale.

Analysis will determine the associations between changes in brain glutamate, GABA and perfusion levels and symptomatic response to clozapine. In a second analysis we will determine these neuroimaging variables at baseline are predictive of subsequent response, using multivariate pattern recognition analysis will be used to classify the cases according to clinical outcome (response versus non-response).

This research will aid the development of new (non-dopamiergic) antipsychotics, and biomarkers to predict response to clozapine or stratify patients in clinical trials of new drugs.

The potential beneficiaries from this work are as follows:
1) PATIENT AND CARERS
The ultimate aim of this research is to improve treatment for people with schizophrenia. We hope to do this in several ways.
First, by providing information for the rational development of new drugs to treat schizophrenia. This project specifically addresses a patient population who do not respond well to the currently available medications, and aims to find new targets for novel approaches.
Second, this research will determine whether MRI scans can predict in advance whether or not a particular patient will respond to clozapine. This means that patients who will do well on clozapine could be given it earlier, while side effects could be avoided in those unlikely to benefit. This would ultimately improve the health of this patient group. Furthermore if the approach is successful, it could be applied to other medications or other mental health disorders.
Third, if the MRI scans provide biomarkers of treatment response, this could be used to stratify patients in clinical trials which would expedite drug development for this group.
Achieving these aims will require engagement with the pharmaceutical industry and academic community.
2) ACADEMIC RESEARCH COMMUNITY
The ways in which the academic community will benefit from this research are included in the section 'Academic Beneficiaries'
3) INDUSTRY
As described above, it is hoped that this research will lead to new targets for drug development and biomarkers to stratify patients in clinical trials. New drug development in schizophrenia is currently a key focus for industry.
4) CLINICIANS
If information from MRI scans can be used to help predict response, this would aid clinical decision making in a difficult area. The decision to put a patient on clozapine is not easy, as clozapine may not work and is potentially associated with lethal adverse effects, thus requiring regular monitoring and resources. For this reason trials of clozapine are often delayed, and suboptimal treatment strategies employed meantime. If the availability of such a test could increase confidence that clozapine would be effective, this would help decision making and clinicians would be encouraged to try clozapine earlier. Likewise, if tests show clozapine was unlikely to be helpful in a particular patient, this would provide a rational basis for trying other options first.
6) GENERAL PUBLIC
This research addresses management of treatment resistant schizophrenia. These are among the most unwell of mental health patients, who require high health and social care resources, are over-represented in forensic psychiatry settings and who seldom return to work. Improving the health of this patient group will therefore have positive societal and socioeconomic effects.