Marieke Van der Pluijm, University of Amsterdam

Marieke Van der Pluijm image

Treatment resistance in schizophrenia is a major clinical problem with one third of schizophrenia patients showing non-response to standard antipsychotic treatment. The delay in identifying these patients leads to prolonged ineffective treatment, longer hospitalization, unnecessary side effects and lower quality of life for those individuals. There is an urgent need for (bio)markers that can identify treatment-resistant patients early on, enabling timely intervention and improving prognosis.

During my PhD I have developed a keen interest in the neurobiology of psychosis and its relation to treatment response in first episode psychosis. Elucidating the underlying neurobiology of treatment resistance in psychosis could aid in better treatment selection and result in markers for earlier identification of these patients. The core focus of my PhD was the development and application of the novel neuromelanin-sensitive MRI (NM-MRI) technique as a potential clinical marker for treatment resistance. Additionally, I explored alternative markers, including plasma dopa decarboxylase activity as a blood marker and alterations in neurotransmitters, including glutamate and gamma-aminobutyric acid (GABA) levels. These markers hold significance for guiding treatment decisions, particularly in considering clozapine, the antipsychotic recognized for its superior effectiveness in treatment resistant schizophrenia.

At the SIRS 2022 conference, I had the honor to receive an early career award and to present the most notable finding from my PhD including a NM-MRI study in first episode psychosis patients. NM-MRI is a novel non-invasive MRI technique that indirectly measures dopamine functioning. In psychosis research, a common method for evaluating dopamine functioning is [18F]F-DOPA PET imaging, which has consistently shown increased activity in specific brain areas. Interestingly, treatment resistant patients do not show this increased dopamine functioning and show levels comparable to healthy individuals. Unfortunately, [18F]FDOPA PET imaging is expensive and relatively burdensome for patients, since it uses radioactivity and is administered intravenously, making it impractical for widespread use in screening for treatment resistance. NM-MRI as a proxy of dopamine functioning presents a promising alternative due to its non-invasive nature. NM-MRI shows increased signal in schizophrenia patients compared to healthy individuals, but had not yet been tested in treatment resistant schizophrenia. We aimed to determine whether treatment resistant patients show lower NM-MRI signal compared to patients who responded to antipsychotic medication. To accomplish this, we conducted a study in first episode psychosis patients, with a baseline and 6 month follow up measurement. In line with our hypothesis, treatment resistant patients showed significantly lower NM-MRI signal compared to responders, and similar NM-MRI signal compared to healthy individuals. Furthermore, NM-MRI appeared to be relatively robust as NM-MRI signal remained stable over six months follow-up and was not associated with illness duration, medication duration or dosage. These findings provide further evidence for dopaminergic differences between treatment resistant patients and responders, and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia. This study has recently been published in the American Journal of Psychiatry and can be accessed online.

Following our findings that treatment resistant schizophrenia may be associated with a normal dopamine rather than an increased dopamine system, we redirected our attention to another neurotransmitter system: glutamate and GABA. These neurotransmitters are believed to play a role in treatment resistant schizophrenia. As a result, we aimed to further elucidate the roles of glutamate and GABA in the anterior cingulate cortex in first episode treatment resistant schizophrenia. I will present the results of this study as a poster at SIRS 2024 on Thursday.

Currently, I am a post-doctoral researcher at the Department of Psychiatry, Amsterdam UMC in the Netherlands. In this role I contribute to various projects, encompassing both neuroimaging and clinical studies in psychosis. Moving forward, I plan to expand my research endeavors while continuing to lend my expertise to other projects. Over the coming years, my goal is to deepen my understanding and experience in the field of psychosis. Eventually I want to use my accumulated expertise to pursue grants and establish my own research program dedicated to improving diagnostics and treatment for early psychosis.

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