Schizophrenia is a severe mental disorder with a significant health burden globally and for up to a third of patients, the current drugs and treatments do not work. As a result, there is a real need to understand the biology and the physiology behind schizophrenia so more effective treatments can be developed.

Dopamine is a chemical called a neurotransmitter. It helps in the transmission of signals from neuron to neuron, particularly in the brain. When these types of neurons are hyperactive in a particular region of the brain called the striatum, it is thought to underlie the symptoms of schizophrenia, particularly the psychosis. Therefore, to understand the neurobiology behind this disease, this situation needs to be mimicked in the lab so new potential treatments can be tested also.

Researchers from our Psychiatric Imaging group report in the journal Molecular Psychiatry the development of a mouse model that replicates this physiology behind schizophrenia; and is the first model to reproduce that seen in patients. Humans who take ketamine develop schizophrenia-like symptoms. Ketamine-treated mice in the model they developed showed brain dopamine changes that mimic changes seen in the brains of these patients including an increase in dopamine activity in a specific region of the brain; the striatum.

With the development of a physiological model of schizophrenia, new drugs to treat the disorder could be tested. Our colleagues explore whether this increase in dopamine activity could be reversed with a novel drug compound called SEP-363856. The administration of this compound causes a reduction in dopamine levels in the ketamine-treated mice. These observations suggest that this mouse model can mimic the physiology of the disease but also that it can be targeted and can be useful for testing new therapeutic approaches.

Michelle Kokkinou, first author on this study, shared more about the next steps:

“Now we have developed this translational mouse model, we want to try and delve a little deeper into the molecular and circuit mechanisms and answer why there is an increase in dopamine in schizophrenia patients. The more we know about the mechanism, the better our understanding will be when it comes to developing novel agents with anti-psychotic potential”.

Oliver Howes, Head of the Psychiatric Imaging group and senior author on this study, said:

“We desperately need to understand the mechanism underlying schizophrenia to develop better treatments. Back-translation, as we did here, is rarely done but is essential if we are to develop better treatments. Our findings have identified a novel approach to target the biology underlying schizophrenia, and this is something we are now testing in patients”.

‘Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine’ was published in Molecular Psychiatry on 7 May. Read the full article here.