The role of glutamatergic function in the pathophysiology of treatment-resistant schizophrenia and the potential of novel treatment targeting it

Schizophrenia affects 1 in 100 people and is a chronic and disabling psychiatric illness.
Antipsychotic drugs are the first-line treatment for schizophrenia. However, they are ineffective for many patients. Patients who do not respond to two or more antipsychotic treatments of adequate dose and duration are said to have treatment-resistant schizophrenia (TRS). TRS is common, affecting about one third of patients, and is associated with worse quality of life, longer hospital admissions, and worse functioning than in schizophrenia in general. Schizophrenia costs, which in the UK are estimated to be £11.8 billion per year, are also 3 to 11-fold higher in TRS.

Clozapine is the only antipsychotic that has been licensed for the treatment of TRS. However, its use is limited by poor tolerability, life-threatening side-effects and requirements for frequent blood monitoring. In fact, less than one third of TRS patients receive clozapine. Moreover, even when it is used, many patients show inadequate response to clozapine.

Given these limitations, there is a clear need for alternative medications for TRS. However, the lack of understanding of the neurobiology of TRS has been a major impediment to finding novel treatments for TRS.

In recent years several imaging studies have suggested that TRS has a different underlying neurobiology to that seen in patients who respond to non-clozapine antipsychotics. While changes in dopamine transmission usually seen in schizophrenia are absent in TRS, levels of another neurotransmitter called glutamate have are increased, particularly in a brain region called the anterior cingulate cortex (ACC). This suggests that a different underlying mechanism may underlie TRS.

Taken together, this evidence implicates the glutamate system in the neurobiology of TRS, and indicates that targeting glutamate could be a new approach to treatment. However, it is still unknown if glutamate underlies TRS or if targeting glutamate levels could be an effective treatment. The key test is to reduce glutamate levels and determine the effect on symptoms.

To achieve this purpose we aim to use a drug called riluzole that reduces brain glutamate levels. There is preliminary evidence from a small clinical study that riluzole may improve symptoms in TRS. Moreover, in a pilot study conducted by our research group we showed that riluzole reduces glutamate levels in patients with TRS. However, this study did not test if reducing glutamate levels led to a reduction in symptoms, and the clinical study needs replication in patients with confirmed TRS.

In this proposal we plan to test two critical gaps in knowledge. The first is whether brain glutamatergic function is central to the pathophysiology of TRS. The other is whether it is possible to reduce glutamate levels in TRS and if this will improve symptoms.
To answer these questions we will use an imaging technique called magnetic resonance spectroscopy (MRS) to measure glutamate levels in the ACC of TRS patients. We will use a randomised, double-blind placebo controlled design. Patients with TRS will receive a baseline scan and then riluzole or placebo for a period of 56 days and follow-up scans at this point in order to: i) determine if treatment with riluzole leads to a reduction in glutamate levels, as assessed via MRS imaging, when compared to placebo; ii) determine if riluzole improves symptoms relative to placebo, and iii) if change in glutamate levels is directly associated with a reduction in symptom severity.

This study will provide critical evidence of the potential to target the glutamate system for the treatment of TRS, improve our understanding on the neurobiology of TRS, and finally will help guide the development of new drugs targeting the glutamate system for the treatment of TRS.

Treatment-resistant schizophrenia (TRS) occurs in approximately 30% of patients with schizophrenia. Clozapine is the only approved medication for TRS but is poorly tolerated, has serious side-effects, and is not effective for many patients, leaving large numbers of patients without an effective treatment.

Evidence indicates patients with TRS do not show dopamine dysregulation, in contrast to patients with schizophrenia who respond to first-line antipsychotics. Instead they show glutamatergic dysfunction. Specifically, glutamate and Glx levels have been shown to be elevated in the anterior cingulate cortex (ACC), as assessed by magnetic resonance spectroscopy (MRS), in TRS patients when compared to responders and controls. However, these studies were cross-sectional so they cannot show causality, and therefore it is still unknown if glutamate plays a primary role in the symptoms and brain changes seen in TRS. The key test is to ameliorate glutamate abnormalities and determine if this leads to an improvement in symptoms.

To achieve this purpose we will use riluzole, a drug that reduces pre-synaptic glutamate release. Importantly, we showed in a small proof-of-concept study that riluzole reduces glutamate/Glx levels in the ACC in TRS patients. However, this study did not test if reducing glutamate indices led to a reduction in symptoms.

We will use a double-blind study design to randomise patients to riluzole or placebo for a period of 56 days. We will measure glutamate/Glx in the ACC of TRS patients at baseline and at the end of the study. Results from this study will be fundamental to: i) determine if riluzole will lead to a reduction in glutamate indices when compared to placebo; ii) if reduction in glutamate indices are associated with a reduction in symptom severity when compared to placebo.

The study will provide critical information on the role of glutamate in the neurobiology of TRS and the potential of glutamatergic drugs to treat TRS.