Back in control: Towards early identification of treatment resistance in schizophrenia

Treatment-resistance in schizophrenia is a major clinical problem, with 20-35% of patients showing no response to first-line antipsychotic treatment. This results in delays in effective treatment, which can lead to longer hospitalization, unnecessary side effects, and functional disabilities. Therefore, there is an urgent need for (bio)markers that could identify treatment-resistant patients to guide treatment decision. Increased striatal dopamine synthesis is a well-known finding in schizophrenia, but treatment-resistant patients do not show this increase. However, the gold standard for assessing dopamine synthesis (positron emission tomography imaging) is too expensive and burdensome for patients to be used for screening. Hence, the aim of this thesis is to investigate other potential markers for earlier identification of treatment-resistant schizophrenia. The primary emphasis of this thesis is the development and application of the novel neuromelanin-sensitive MRI sequence (NM-MRI), which indirectly measures dopamine synthesis. In addition, we explored other potential markers, including plasma dopa-decarboxylase activity and glutamatergic or gamma-aminobutyric acid (GABA) alterations.
We demonstrate that NM-MRI has potential as a marker for treatment resistance. Furthermore, we have established the reproducibility of NM-MRI and show that the acquisition could be reliably accelerated. We have summarized evidence that in-vivo imaging of the substantia nigra is important in schizophrenia, and gained more insight into how NM-MRI relates to dopamine synthesis capacity. A recently developed plasma measure of dopa-decarboxylase activity, an enzyme involved in dopamine synthesis, showed no promise as marker. Glutamate and GABA levels in the anterior cingulate cortex were also not associated with treatment resistance.