Glutamate-Energetics In Schizophrenia And Treatment Resistance

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Sept. 30, 2023

Sept. 30, 2027

Schizophrenia is severe mental health condition. Symptoms vary from person to person, but can include hallucinations, having unusual thoughts or beliefs that are not based on reality, muddled thinking, loss of interest in everyday activities or avoiding social contact. Antipsychotic medication is effective in reducing the symptoms of schizophrenia, but unfortunately in around a third of people symptoms will fail to improve. When symptoms do not improve following adequate treatment with two different antipsychotic medications, this can be termed treatment resistant schizophrenia. Furthermore, while some symptoms generally respond well to medication, other symptoms including cognitive impairments (such as poor memory) may persist and negatively impact on everyday life. There is a substantial need for new medicines to treat schizophrenia.

The causes of schizophrenia are unknown and are likely to involve more than one factor. One of the leading theories is that schizophrenia is related to changes in glutamate, which is the main excitatory neurotransmitter in the brain. There is also early evidence that changes in glutamate could be particularly important in those who experience more severe symptoms and treatment resistance. There is therefore scientific interest in developing new medicines that work on the glutamate system, although these have not yet been successful.

Regulation of glutamate neurotransmission is by far the most energy demanding process in the brain. These energy demands are met through supply of glucose, which is the brain's main source of energy. When energy demands are high, lactate may provide a supplementary energy source. This ability to meet energy demands and regulate glutamate neurotransmission is a fundamental biological process, vital for healthy brain functioning and cognition. Our theory is that this process is not working optimally in schizophrenia.

Although there is good scientific understanding of glutamate and energy use, the relationships between glutamate, glucose utilisation and lactate production have not been measured in the living human brain before. We will do this by acquiring two types of brain scans (called MRI and PET) in people with and without schizophrenia. We propose that in schizophrenia, changes in glutamate are associated with an additional energy demand which the brain struggles to meet, and that this is most apparent in those with treatment resistant illness. We hope that this knowledge may help to identify new avenues for research aimed at developing novel medicines for schizophrenia.

Technical Abstract:
Development of new therapeutics for schizophrenia requires a deeper understanding of the underlying neurobiological processes. It is long-established that the efficacy of standard antipsychotics principally relates to dopamine receptor blockade. Less is known about the mechanisms that contribute to treatment resistant schizophrenia (TRS), and which could provide modifiable targets for intervention. Substantial evidence implicates glutamate in the neurobiology of schizophrenia. Recently, this has extended to neuroimaging studies linking elevated glutamate levels to TRS and greater symptom burden.

Regulation of glutamate release, reuptake and recycling is critical for healthy cortical function carries high energy demand, accounting for 75-80% of total cortical glucose consumption. Lactate may provide a supplementary energy source when the energy demands to sustain glutamate cycling are high. We propose that in schizophrenia, prolonged attempts to meet the increased energy demands associated with glutamate dysfunction leads to a pathophysiological shift in brain energetics. We also propose that this pathophysiological shift will be most apparent in TRS, associated with greater symptom severity and worse functioning and cognition.

Although there is considerable biochemical understanding of glutamate-energetic processes from preclinical science, the relationships between glutamate, glucose utilisation and lactate production have not been studied in the living human brain before within the same participants. We will do this by applying state-of-the-art neuroimaging techniques in healthy volunteers and in people with schizophrenia. The insights into glutamate-energetics provided by our study may provide new avenues for research and ultimately for therapeutic development for schizophrenia and other brain disorders.