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Treatment resistance (TR) in schizophrenia is a major clinical problem with 20-35% of psychotic patients showing non-response to antipsychotic treatment. This leads to months to years of delay in effective treatment, resulting in hospitalization and unnecessary side effects of ineffective antipsychotics. We need a biomarker that could be used to switch TR patients at an early stage to clozapine, the only antipsychotic with recognized superior effectiveness in TR.

A well-established finding in schizophrenia, using [18F]F-DOPA positron emission tomography (PET) imaging, is increased striatal dopamine synthesis, but interestingly TR patients don’t show altered synthesis. PET imaging however is too costly and invasive to use for TR screening. A novel neuromelanin-sensitive MRI sequence (nMRI), which indirectly measures striatal dopamine synthesis, and which I first used when at Columbia University, has great potential as biomarker for TR. nMRI indeed shows increased signal in schizophrenia patients, but has not yet been tested in TR. Another potential biomarker is a recently developed plasma measure of dopa decarboxylase (DDC) activity, an enzyme required for dopamine synthesis. Furthermore, the role of other neurotransmitters than dopamine in TR is underexposed, of which glutamate is a likely candidate.

I will determine whether the novel nMRI sequence and/or plasma DDC activity measure are suitable biomarkers for TR in schizophrenia and explore the role of glutamate as potential biomarker. Therefore, I will acquire nMRI scans, plasma samples for DDC activity and glutamate magnetic resonance spectroscopy (MRS) in 100 first episode psychosis patients and follow them for 6 months to assess TR. I will also acquire [18F]F-DOPA PET scans in a subgroup of patients.

If nMRI, plasma DDC activity and possibly glutamate MRS are good biomarkers for TR, I want to develop these as clinical tools in the future, in order to provide appropriate treatment for TR patients at an early stage.

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