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Clozapine Treatment May Reduce Glutamate Levels in Caudate Nucleus

January 25, 2021

A longitudinal study recently published in Schizophrenia Bulletin found that symptom improvements in people with treatment-resistant schizophrenia who switch to clozapine may be related to reductions in glutamate in the caudate nucleus. Here, researcher Alice Egerton, PhD, of King's College London in the United Kingdom, explains the reasons for the research, how the findings were reached, and one surprising finding of the study. 

Q: Why did you and your colleagues decide to look into how clozapine affects glutamate in the brain?

A: For most people with schizophrenia, antipsychotic medication is effective in reducing symptom severity. Unfortunately, in a minority of patients, symptoms do not respond adequately to conventional antipsychotic treatments. This subgroup may go on to be termed as having treatment-resistant illness. Clozapine is the only recommended treatment for this subgroup, as it can improve symptoms when other antipsychotics have failed.

The biological mechanisms that underlie clozapine’s efficacy are unclear. If we understood this more fully, it might help with developing alternative treatment strategies, or perhaps even identifying patients who are most likely to benefit from clozapine earlier in their illness.

Previous research had provided some initial indications that the efficacy of clozapine may be related, at least in part, to its effects on the brain glutamate system. In our study, we aimed to investigate this more directly, by examining whether changes in glutamate occur in selected brain regions after a patient is switched from treatment with a conventional antipsychotic to treatment with clozapine.

Q: Please briefly describe your study method and key findings.

A: Our study recruited patients with treatment-resistant schizophrenia who were about to switch to clozapine as part of their normal clinical care. We measured the amount of glutamate in 2 brain regions, the anterior cingulate cortex and the caudate, before switching to clozapine and again after 12 weeks of clozapine treatment. Glutamate was measured during a magnetic resonance imaging (MRI) scan, using a technique called proton magnetic resonance spectroscopy (1H-MRS). Symptoms were monitored over the study period. Twenty-five people with treatment-resistant schizophrenia completed the MRI scans both before and after 12 weeks of clozapine treatment.

The main finding of our study was that over 12 weeks of clozapine treatment, glutamate levels were reduced in the caudate, but not in the anterior cingulate cortex. The reduction in glutamate in the caudate was also associated with the percentage improvement in symptoms over the study period. This could suggest that clozapine’s ability to reduce glutamate in the caudate may contribute to the improvements in symptoms that are observed in the first months after switching to clozapine.

Q: Were any of the outcomes unexpected or surprising?

A: We had expected that clozapine treatment would be associated with a reduction in glutamate in the anterior cingulate cortex, as well as in the caudate nucleus. Instead we found that anterior cingulate glutamate levels appeared relatively stable during the first 3 months of clozapine treatment. It may be that clozapine does not have a strong effect on glutamate levels in the anterior cingulate cortex. Alternatively, it could be that this effect emerges after a longer period of taking clozapine and when symptoms are further improved. Future studies with a longer follow-up period would be able to address this question.

Q: Do these findings have any applications in clinical practice?

A: Our study does not have any direct applications in clinical practice. However, in the future, we plan to extend this work, including to investigate whether MRI scans and other biological measures can predict how well someone is likely respond to treatment, and to develop novel treatments for those patients in whom symptoms are not adequately addressed by the currently available medications.

Q: Are you conducting any follow-up research in this area, and are there any other studies you feel are needed?

A: While our study focused on glutamate, the efficacy of clozapine is likely due to multiple interacting processes that occur across brain regions. We are currently using complementary techniques to examine some of these other processes, such as changes in brain network activity, that may occur during clozapine treatment and contribute to symptomatic response. Future studies are required to determine whether our findings are consistent across different cohorts of patients taking clozapine, and to investigate the changes in brain neurochemistry and function that underlie longer-term clinical outcomes with clozapine treatment.


McQueen G, Sendt K, Gillespie A, et al. Changes in brain glutamate on switching to clozapine in treatment-resistant schizophrenia. Schizophrenia Bulletin. 2021 January 5;{Epub ahead of print].

Alice Egerton, PhD, is a Reader in Neuropsychopharmacology within the Department of Psychosis Studies at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom. Her research focuses on understanding the biological processes that underlie psychosis and schizophrenia and determine symptomatic response to antipsychotic treatment. These are primarily investigated using magnetic resonance imaging (MRI). With a background in pharmacology, she is particularly interested in the role of glutamate and other neurotransmitter systems in schizophrenia, and how this knowledge may be leveraged to deliver new treatments. Dr. Egerton also leads the MSc in Psychiatric Research program at King’s College London.

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